Use of Ketogenic Compounds for Treatment of Age-Associated Memory Impairment

ABSTRACT

This invention relates to the field of therapeutic agents for the treatment of Age-Associated Memory Impairment (AAMI). In particular, the present invention utilizes compositions comprising at least one compound capable of elevating ketone body concentrations in a mammal (e.g., ketogenic compounds), administered in an amount effective for treatment or prevention of loss of cognitive function caused by reduced neuronal metabolism in AAMI. In one embodiment, the composition includes medium chain triglycerides (MCT). In another embodiment, the compositions are administered in the presence of carbohydrate. The present invention also relates to oral dosage forms, in particular, a nutritional drink comprising at least one compound capable of elevating ketone body concentrations in a mammal.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/358,257, filed Jan. 25, 2012 entitled, “Use of Ketogenic Compoundsfor Treatment of Age-Associated Memory Impairment,” which is acontinuation of U.S. application Ser. No. 12/064,850, filed Apr. 24,2008 entitled, “Use of Ketogenic Compounds for Treatment ofAge-Associated Memory Impairment,” which is a 35 U.S.C. §371 nationalphase application of PCT/US07/65873 (WO 2007/115282), filed on Apr. 3,2007 entitled “Use of Ketogenic Compounds for Treatment ofAge-Associated Memory Impairment,” which application claims the benefitof U.S. Provisional Application Ser. No. 60/744,140 filed Apr. 3, 2006entitled “Use of Medium Chain Triglycerides for the Treatment andPrevention of Age-Associated Memory Impairment,” each of which areincorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Aging causes deterioration of various aspects of physiology in normaladults, including memory performance. Such age related declines incognitive performance have long been recognized by medicalpractitioners. Plato and Aristotle (384-322 BC) both wrote about thedeclines in mental performance with age, and how this should be used toexclude aged individuals from certain jobs: “there is not much left ofthe acumen of the mind which helped them in their youth, nor of thefaculties which served the intellect, and which some call judgment,imagination, power of reasoning and memory. They see them graduallyblunted by deterioration and see that they can hardly fulfill theirfunction.”

In more recent times, mental decline has been quantified by a series ofcognitive tests and is now a well accepted phenomenon. Impairment ofmemory performance in the elderly has been detected in several standardmemory tests, including the Wechsler Memory Scale (WMS) and immediateand delayed Visual Reproduction Test (Trahan et al. Neuropsychology,1988 19(3) p. 173-89), the Rey Auditory Verbal Learning Test (RAVLT)(Ivnik, R. J. et al. Psychological Assessment: A Journal of Consultingand Clinical Psychology, 1990 (2): p. 304-312) and others (for reviewsee Larrabee and Crook, Int. Psychogeriatr, 1994 6(1): p. 95-104.

To characterize memory loss more systematically, the National Instituteof Mental Health (NIMH) created a work group which proposed a criteriafor “age-associated memory impairment” (AAMI) (Crook T. H. et al. Dev.Neuropsychol, 1986, 2: p. 261-276.) The criteria for AAMI include,complaints of memory loss in persons over the age of 50 years,impairment on a standardized memory test compared to young adults, andabsence of dementia or any medical condition that could producecognitive deterioration. Because AAMI is related to “normal” aging andnot a pathological condition the prevalence is expected to be high andincrease with increasing age. Recent estimates vary from 18% to 85%,depending on the subjects' age and the population studied.

The clinical course and causes of AAMI are poorly understood. Since AAMIis a part of aging it has frequently been attributed to the generaldeterioration of the body due to cellular damage. Age related increasesin cellular damage are often ascribed to oxidative damage from a varietyof sources. Despite being part of normal aging, several possibletreatments strategies have been attempted to alleviate AAMI and have metwith some success. For example, phosphatidylserine has shown someefficacy in AAMI trials.

The human brain is one of the most metabolically active organs in thebody and requires large amounts of energy for proper function. Cerebraloxygen consumption for an average adult human is roughly 3.5 ml/100g/min. For an average sized brain of 1,400 grams, this is about 40 mlO₂/min. At rest the average person will use ˜250 ml O₂/min. Thereforethe brain uses approximately 16 percent of the total O₂ consumed. Thisis remarkable in that the brain accounts for only about 2 percent of thetotal body mass. Most of the oxygen in the brain is used for theoxidation of glucose. Under normal conditions glucose is primary fuelfor the brain while the contribution of fatty acids is considered minor.The average adult brain consumes approximately 110 grams of glucose aday. The dependence on glucose puts the brain at risk if circulatingglucose levels drop, such that sudden bouts of hypoglycemia causeimpairment of cognitive function. For example, if large amounts ofinsulin are injected this will cause a sudden drop in blood glucose andcognitive dysfunction, including memory problems, sensory disturbancesand even coma.

However under certain conditions when glucose levels are limiting, suchas neonatal development or starvation, the liver will mobilize ketonebodies as a supplemental fuel for the body, and in particular cerebralneurons. Ketone bodies (β-hydroxybutyrate, acetoacetate and acetone) arederived from the incomplete oxidation of fatty acids by both hepatocytesand glial cells, and released into the bloodstream to provide asupplement to glucose. Ketone bodies cannot fully substitute forglucose, but can account for a significant fraction of cerebralmetabolism. In early studies conducted on fasting of obese humansubjects, considerable uptake of ketone bodies into the brain wasobserved. The uptake was sufficiently large to account for almost 50% oftotal cerebral O₂ usage.

The ability of ketone bodies to supplement glucose in the brain has beenused to treat conditions of low glucose availability to the brain. GLUT1is a constitutive glucose transporter that transports glucose into thecentral nervous system (CNS). The high glucose requirement of the brainrequires that two functional copies of the GLUT1 gene be present. If onecopy of GLUT1 is non-functional this results in GLUT1 deficiencysyndrome. The resulting low glucose levels during development lead toinfant seizures, delayed development and microcephaly. Partial relief ofthese symptoms can be achieved by increasing serum ketone levels byadministration of a ketogenic diet. Thus, if glucose uptake or use islimited, ketone bodies may serve to supplement energy requirements.

One physiological hallmark of aging in mammals is a decreased uptake andmetabolism of glucose within the brain. The impaired glucose metabolismin the brain may contribute or exacerbate the cognitive deficitsobserved during normal aging. Facilitation of memory in elderly subjectsoccurs when glucose levels are elevated by the administration ofcarbohydrate. However, such a treatment poses challenges since elevatedblood glucose levels are difficult to maintain and must be within arelatively narrow window, as excessive hyperglycemia is associated withcognitive impairments. Therefore it is important to explore otheraspects of the model.

Substantial scientific evidence has shown that defects in cerebralglucose metabolism occur during aging in several mammalian species. Aseries of studies done in the 1980s demonstrated decreased cerebralglucose metabolism in aged rats. One study examined the role that thedecreased metabolic rate played in the cognitive decline of aging rats.Aged (22-24 months) and young (3 month) rats were tested in a series ofbehavioral tests including: water maze test (spatial learning), time ona round bridge (motor coordination), open field test (spontaneousactivity) and the startle response. Cerebral glucose utilization wasalso examined in these same rats. As a group, aged animals demonstratedlowered regional glucose utilization when compared with the youngeranimals. The aged group also showed large heterogeneity in extent andregions of decreased glucose metabolism. Interestingly, the amount ofdecreased regional glucose metabolism correlated with impairment incognitive tests. For example, declines in glucose use in the prefrontalcortex correlated well with spatial learning impairment. Similardecreases in glucose metabolism have been observed in rhesus monkeys anddogs.

Early studies in humans using positron emission tomography failed tofind evidence of decreased cerebral glucose metabolism in normal agedsubjects. However, more recent studies employing more sensitivetechniques and instrumentation have found that regional decreases inglucose metabolism are associated with normal human aging. In a study of25 healthy volunteers between the ages of 20 to 68, total oxygenconsumption in the brain was found to be reduced approximately 6% perdecade. Importantly, the decline still was evident when cortical atrophywas included in the calculations, demonstrating that the decreases inmetabolism are not simply due to cell loss. Others have mapped thedecreases in metabolism to specific regions of the brain to create a“metabolic topography of normal aging”. This map located metabolicdecline to largely frontal regions of the brain and represented anapproximately 12% decrease in global metabolic rate between the ages of20 and 80.

Attempts to improve memory performance in the elderly by increasingglucose availability have met with some success in both animal modelsand in humans. For example, in a Y maze test, both young and old micenormally enter the new arm if there is no delay when the animals areplaced in the maze. This is a measure of spontaneous alteration. If,however, a delay of 1 minute is used, young mice (2 month) still performwell on this task but old mice (2 year) do not. Yet, if the mice aregiven glucose before the test, the old mice perform as well as the youngmice, and there is no increase in the ability of the young mice (Stone,W. S., et al., Glucose attenuation of deficits in spontaneousalternation behavior and augmentation of relative brain 2-deoxyglucoseuptake in old and scopolamine-treated mice, Psychobiology, 1992,20:270-279). This is consistent with studies in humans that have largelyshown increases in cognition following glucose administration in elderlygroups but not for young groups. In one study, two sets of subjects, oneyoung (mean age 20 years old) and one elderly (mean age 67 years old)were given either a sugar free lemon drink sweetened with artificialsweeteners (0 g carbohydrates) or a drink sweetened with sugar (50 gcarbohydrate) on alternate visits in a crossover design. On each visitthe subjects were given a series of cognitive tests, including a pairedassociation task, a test of contextual memory, a test of immediaterecall, and a test of visual memory. The glucose improved the scores ofthe elderly group but not the young group. Such experiments have beenreplicated several times and seem to indicate that memory facilitationby glucose is characterized by an inverted-U shape, with too muchglucose negating the effect.

The mechanism for increased memory after glucose administration is stillunclear but may be related to increased energy production and thecorresponding increased acetylcholine production. Yet, glucose may notbe a practical means to elevate memory in the aged for several reasons.(1) Elevated glucose levels are difficult to maintain in a healthymammal. (2) Hyperglycemia may improve memory but may prove detrimentalto other organ systems. (3) Elevated blood glucose may lead tochronically elevated insulin levels and the problems associated withhyperinsulinemia.

Interestingly other substrates may also facilitate memory in agedanimals. For example, morphine is known to impair memory formation yetthis effect can be blocked by co-administering glucose. Similarlypyruvate can also block the effects of morphine administration.

There has been long experience with ketogenic diets, which mimicstarvation, in children treated for epilepsy. The diet is a medicaltherapy and should be used under the careful supervision of a physicianand/or dietician. The diet carefully controls caloric input and requiresthat the child eat only what has been included in the calculations toprovide 90% of the day's calories as fats. However, such diets aregenerally unsuitable for use in adults due to: (1) adverse effects onthe circulatory system from incorporation of cholesterol and long chaintriglycerides as the primary fat in these diets; (2) poor patientcompliance due to the unappealing nature of the low carbohydrate diet.

The prior art provides descriptions of ketogenic diets in which fat ishigh and carbohydrates are limited. In summary, the rationale of suchdiets is that intake of high amounts of fat, whether long-chain ormedium-chain triglycerides can increase blood ketone levels in thecontext of a highly-regimented diet in which carbohydrate levels areabsent or limited. Limitation of carbohydrate and insulin are believedto prevent re-esterification in adipose tissue. Although the ketogenicdiet has been known for decades, there does not appear to be any priorart teaching or suggesting that MCT therapy be used to treat diseases ofreduced neuronal metabolism in patients with any age-associatedcognitive decline, such as AAMI, and the like.

There is thus a need in the art to develop compositions and methods forthe treatment and/or prevention of cognitive impairment, particularly inaging or geriatric mammals such as humans.

Various publications, including patents, published applications,technical articles and scholarly articles are cited throughout thespecification. Each of these cited publications is incorporated byreference herein, in its entirety. Full citations for publications notcited fully within the specification are set forth at the end of thespecification.

SUMMARY OF THE INVENTION

In one embodiment, the present invention includes compositions compoundscapable of elevating ketone bodies in a mammal, such as, for example,medium chain triglycerides (MCT), including a nutritional drink for oralconsumption comprising: a unit dose sufficient to a) raise blood levelsof D-β-hydroxybutyrate to about 0.1 to about 5 mM or b) raise urinaryexcretion levels of D-β-hydroxybutyrate to about 5 mg/dL to about 160mg/dL; L-carnitine, a plurality of vitamins; flavoring, and acarbohydrate source and wherein the MCT, if included, are of theformula:

wherein the R1, R2, and R3 esterified to the glycerol backbone are eachindependently fatty acids having carbon chains of 5-12 carbons.

In another embodiment, the present invention includes a method oftreatment for Age-Associated Memory Impairment (AAMI), comprising thesteps of identifying a mammal having, or at risk of AAMI; andadministering to the mammal a composition comprising at least onecompound capable of elevating ketone body concentrations in an amounteffective for the treatment of or prevention of loss of cognitivefunction caused by reduced neuronal metabolism in AAMI.

The present invention also relates to a method for treatment of agerelated cognitive decline or AAMI, comprising the steps of identifying apopulation of healthy aging mammals having AAMI, dividing the populationinto at least a control group and one or more test groups, formulatingat least one delivery system for delivering a composition comprising atleast one compound capable of elevating ketone body concentrations in anamount effective for elevating at least one type of ketone body in theblood of an individual mammal, wherein, on an extended regular basis,each test group receives a formulation delivering a compositioncomprising at least one compound capable of elevating ketone bodyconcentrations and the control group does not receive any compositioncomprising at least one compound capable of elevating ketone bodyconcentrations. The method further comprises comparing at least oneneuropsychological test result in the control and test groups,determining which of the delivery systems for delivering the compositioncomprising at least one compound capable of elevating ketone bodyconcentrations was effective in improving the results of at least oneneuropsychological test; and administering a treatment-based deliverysystem determined in the previous step to a population of aging mammals,thereby treating AAMI.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the improvement of mental performance, as measured by theimprovements in Memory Scanning Reaction Time for all set sizes for anAAMI cohort.

FIG. 2 shows the improvement of mental performance, as measured by theimprovements in Memory Scanning Reaction Time for all set sizes for anAAMI cohort.

DETAILED DESCRIPTION OF THE INVENTION

It is the novel insight of this invention that compositions comprisingat least one compound capable of elevating ketone body concentrations,such as, for example, medium chain triglycerides (MCT) and or mediumchain fatty acids (MCFA), are useful as a treatment and preventativemeasure in patients with any age-associated cognitive decline, such asAAMI, and the like. These conditions are associated with reducedneuronal metabolism. As used herein, reduced neuronal metabolism refersto all possible mechanisms that could lead to a reduction in neuronalmetabolism. Such mechanisms include, but are not limited tomitochondrial dysfunction, free radical attack, generation of reactiveoxygen species (ROS), ROS-induced neuronal apoptosis, defective glucosetransport or glycolysis, imbalance in membrane ionic potential,dysfunction in calcium flux, and the like.

In light of the deficiencies for other methods to treat deficits ofenergy metabolism in the brain, discussed hereinabove, the presentinvention contemplates use of another substance to improve memoryperformance, in particular, ketone bodies, which is known to be readilyutilized by the brain.

Ketone bodies, in particular β-hydroxybutyrate (βHB) and acetoacetateserve a critical role in the development and health of cerebral neurons.Numerous studies have shown that the preferred substrates for thedeveloping mammalian neonatal brain are ketone bodies. There is a largebody of evidence demonstrating that ketone bodies are used in aconcentration dependent manner by the adult human brain, even in theelderly. Ketone bodies (KB) offer several advantages to glucose formemory facilitation in the elderly. (1) KB can be artificially elevatedby the administration of large amounts of medium chain triglycerides(MCT) without altering glucose levels. (2) Hyperketonemia can be inducedand sustained for many hours. (3) KB readily cross the blood brainbarrier. (4) KB are readily metabolized by cerebral neurons and can beused to generate ATP and acetylcholine. In particular, a compositiondeveloped by the inventors, Ketasyn™, provides a simple and safe methodto induce hyperketonemia.

The active ingredient of Ketasyn™ is MCT. MCT are comprised of fattyacids with chain length between 5-12 carbons and have been researchedextensively. MCT are metabolized differently from the more common LongChain Triglycerides (LCT). In particular, when compared to LCT, MCT aremore readily digested to release medium chain fatty acids (MCFA) whichexhibit increased rates of portal absorption, and undergo obligateoxidation. MCFA have melting points much lower than long chain fattyacids (LCFA), and therefore the MCFA and corresponding MCT are liquid atroom temperature. MCFA are smaller and more ionized at physiological pHcompared to LCFA, and hence MCFA are much more soluble in aqueoussolutions. The small size and decreased hydrophobicity of MCT increasesthe rate of digestion and absorption relative to LCT.

When ingested, MCT are first processed by lipases, which cleave thefatty acid chains from the glycerol backbone. Some lipases in thepre-duodenum preferentially hydrolyze MCT over LCT and the released MCFAare then partly absorbed directly by the stomach mucosa. Those MCFAwhich are not absorbed in the stomach are absorbed directly into theportal vein and not packaged into lipoproteins. LCFA derived from normaldietary fat are re-esterified into LCT and packaged into chylomicronsfor transport in the lymph. This greatly slows the metabolism of LCTrelative to MCT. Since blood transports much more rapidly than lymph,MCFA quickly arrive at the liver.

In the liver MCFA undergo obligate oxidation. In the fed state LCFAundergo little oxidation in the liver, due mainly to the inhibitoryeffects of malonyl-CoA. When conditions favor fat storage, malonyl-CoAis produced as an intermediate in lipogenesis. Malonyl-CoAallosterically inhibits carnitine palmitoyltransferase I, and therebyinhibits LCFA transport into the mitochondria. This feedback mechanismprevents futile cycles of lipolysis and lipogenesis. MCFA are, to alarge extent, immune to the regulations that control the oxidation ofLCFA. MCFA enter the mitochondria without the use of carnitinepalmitoyltransferase I, therefore MCFA by-pass this regulatory step andare oxidized regardless of the metabolic state of the organism.Importantly, since MCFA enter the liver rapidly and are quicklyoxidized, large amounts of ketone bodies are readily produced from MCFAand a large oral dose of MCT (roughly 20 mL) will result in sustainedhyperketonemia. It is the novel insight of the inventor that MCT may beadministered outside of the context of a ketogenic diet. Therefore, inthe present invention carbohydrates may be consumed at the same time asMCT. This represents a significant advantage over the prior art, whichonly describes the use of MCT in the context of a ketogenic diet. Suchdiets greatly restrict both carbohydrate and protein in the diet andare, in practice, extremely difficult for patients to comply with. Thepresent invention represents a significant advantage over ketogenic dietprior art, in that in the present invention the subject is free followany diet and does not have to adhere to any dietary restrictions.

According to the present invention, high blood ketone levels willprovide an energy source for brain cells that have compromised glucosemetabolism, via the rapid oxidation of MCFA to ketone bodies, leading toimproved performance in, and/or reversal, prevention, reduction, and/ordelaying of decline in one or more of cognitive function, memory, motorperformance, cerebrovascular function, and/or behavior. As used herein,“patient” refers to any mammal, including humans that may benefit fromtreatment of disease and conditions resulting from reduced neuronalmetabolism.

Various terms relating to the methods and other aspects of the presentinvention are used throughout the specification and claims. Such termsare to be given their ordinary meaning in the art unless otherwiseindicated. Other specifically defined terms are to be construed in amanner consistent with the definition provided herein.

The background of this invention supports the present invention in thefollowing ways. (1) Neurons of the brain can use both glucose and ketonebodies for respiration. (2) The neurons of patients with age-associatedcognitive decline, such as AAMI, may have defects in glucose metabolism.(3) Aging may cause defects in metabolism that may underliesusceptibility to any age-associated cognitive decline, such as AAMI,and the like. Hence, supplementation of patients with any age-associatedcognitive decline, such as AAMI, and the like with MCT will restoreneuronal metabolism.

In one embodiment, a compound capable of elevating a ketone bodyconcentrations in the body of a mammal include “medium chaintriglycerides” or “MCT”, referring to any glycerol molecule ester-linkedto three fatty acid molecules, each fatty acid molecule having a carbonchain of 5-12 carbons. MCT may be represented by the following generalformula:

where R1, R2 and R3 are fatty acids having 5-12 carbons in the carbonbackbone esterified to the a glycerol backbone. The structured lipids ofthis invention may be prepared by any process known in the art, such asdirect esterification, rearrangement, fractionation,transesterification, or the like. For example, the lipids may beprepared by the rearrangement of a vegetable oil such as coconut oil.The length and distribution of the chain length may vary depending onthe source oil. For example, MCT containing 1-10% C6, 30-60% C8, 30-60%C10, 1-10% C10 are commonly derived from palm and coconut oils. MCTcontaining greater than about 95% C8 at R1, R2 and R3 can be made bysemi-synthetic esterification of octanoic acid to glycerin. Such MCTbehave similarly and are encompassed within the term MCT as used herein.

“Effective amount” refers to an amount of a compound, material, orcomposition, as described herein that is effective to achieve aparticular biological result. Such results include, but are not limitedto, at least one of the following: enhancing cognitive function,improving memory, improving liver function, increasing daytime activity,improving learning, improving attention, improving social behavior,improving motor performance, and/or improving cerebrovascular function,particularly in aging or geriatric mammals. In various embodiments,“effective amount” refers to an amount suitable to reverse, reduce,prevent, or delay a decline in the above qualities, for example,cognitive function or performance, memory, learning rate or ability,problem solving ability, attention span and ability to focus on a taskor problem, motor function or performance, social behavior, and thelike. Preferably the reversal, prevention, reduction, or delay of adecline in an individual or population is relative to a cohort—e.g. acontrol mammal or a cohort population that has not received thetreatment. Such effective activity may be achieved, for example, byadministering the compositions of the present invention to a mammal orto a population of mammals.

Effectiveness for treatment of the aforementioned conditions may beassessed by improved results from at least one neuropsychological test.These neuropsychological tests are known in the art and include ClinicalGlobal Impression of Change (CGIC), Rey Auditory Verbal Learning Test(RAVLT), First-Last Names Association Test (FLN), Telephone Dialing Test(TDT), Memory Assessment Clinics Self-Rating Scale (MAC-S), Symbol DigitCoding (SDC), SDC Delayed Recall Task (DRT), Divided Attention Test(DAT), Visual Sequence Comparison (VSC), DAT Dual Task (DAT Dual), andGeriatric Depression Scale (GDS), among others.

The term “cognitive function” refers to the special, normal, or properphysiologic activity of the brain, including, without limitation, atleast one of the following: mental stability, memory/recall abilities,problem solving abilities, reasoning abilities, thinking abilities,judging abilities, capacity for learning, perception, intuition,attention, and awareness. “Enhanced cognitive function” or “improvedcognitive function” refers to any improvement in the special, normal, orproper physiologic activity of the brain, including, without limitation,at least one of the following: mental stability, memory/recallabilities, problem solving abilities, reasoning abilities, thinkingabilities, judging abilities, capacity for learning, perception,intuition, attention, and awareness, as measured by any means suitablein the art.

“Behavior” is used herein in a broad sense, and refers to anything thata mammal does in response or reaction to a given stimulation or set ofconditions. “Enhanced behavior” or “improved behavior” refers to anyimprovement in anything that a mammal does in response or reaction to agiven stimulation or set of conditions.

“Decline” of any of the foregoing categories or specific types ofqualities or functions in an individual (characteristics or phenotypes)is generally the opposite of an improvement or enhancement in thequality or function. An “effective amount” (as discussed above) of acomposition may be an amount required to prevent decline altogether orto substantially prevent decline (“prevent” decline), to reduce theextent or rate of decline (“reduce” decline), or delay the onset orprogression of a decline (“delay” a decline), or lead to an improvementfrom a previous decline (“reversal of” or “reversing” a decline).Prevention, reduction, or delay of “decline” is frequently a more usefulcomparative basis when working with non-diseased aging mammals.Reversal, prevention, reduction, and delay can be considered relative toa control or cohort which does not receive the treatment, for example,the composition of interest. Reversal, prevention, reduction, or delayof either the onset of a detrimental quality or condition, or of therate of decline in a particular function can be measured and consideredon an individual basis, or in some embodiments on a population basis.The net effect of reversing, preventing, reducing, or delaying declineis to have less decrease in memory, cognitive, motor, or behavioralfunctioning per unit time, or at a given end point. In other words,ideally, for an individual or in a population, cognitive, motor, andbehavioral functioning is maintained at the highest possible level forthe longest possible time. For purposes herein, an individual can becompared to a control individual, group, or population. A population canlikewise be compared to an actual individual, to normalized measurementsfor an individual, or to a group or population as is useful.

“Aging” as used herein means being of advanced age, such that the mammalhas exceeded 50% of the average lifespan for its particular species.Aging mammals are sometimes referred to herein as “aged” or “geriatric”or “elderly.” Healthy aging mammals are those with no known diseases,particularly diseases relating to loss of cognitive function such asmight confound the results. In studies using healthy aging mammals,cohort mammals are preferably also healthy aging mammals, although otherhealthy mammals with suitable memory, cognitive, motor, or behavioralfunctioning may be suitable for use as comparative specimens. If mammalswith specific disease diagnoses, or memory, cognitive, motor, orbehavioral limitations are used, then the cohort mammals should includemammals that are similarly diagnosed, or which present with similarindicia of the disease or memory, cognitive, motor, or behaviorallimitation.

Administration can be on an as-needed or as-desired basis, for example,once-monthly, once-weekly, daily, or more than once daily. Similarly,administration can be every other day, week, or month, every third day,week, or month, every fourth day, week, or month, and the like.Administration can be multiple times per day. When utilized as asupplement to ordinary dietetic requirements, the composition may beadministered directly to the mammal or otherwise contacted with oradmixed with daily feed or food. When utilized as a daily feed or food,administration will be well known to those of ordinary skill.

Administration can also be carried out on a regular basis, for example,as part of a treatment regimen in the mammal A treatment regimen maycomprise causing the regular ingestion by the mammal of an inventivecomposition in an amount effective to enhance cognitive function,memory, and behavior in the mammal. Regular ingestion can be once a day,or two, three, four, or more times per day, on a daily or weekly basis.Similarly, regular administration can be every other day or week, everythird day or week, every fourth day or week, every fifth day or week, orevery sixth day or week, and in such a regimen, administration can bemultiple times per day. The goal of regular administration is to providethe mammal with optimal dose of an inventive composition, as exemplifiedherein.

The compositions provided herein are, in one embodiment, intended for“long term” consumption, sometimes referred to herein as for ‘extended’periods. “Long term” administration as used herein generally refers toperiods in excess of one month. Periods of longer than two, three, orfour months comprise one embodiment of the instant invention. Alsoincluded are embodiments comprising more extended periods that includelonger than 5, 6, 7, 8, 9, or 10 months. Periods in excess of 11 monthsor 1 year are also included. Longer terms use extending over 1, 2, 3 ormore years are also contemplated herein. In the case of certain agingmammals, it is envisioned that the mammal would continue consuming thecompositions for the remainder of its life on a regular basis. “Regularbasis” as used herein refers to at least weekly, dosing with orconsumption of the compositions. More frequent dosing or consumption,such as twice or thrice weekly are included. Also included are regimensthat comprise at least once daily consumption. The skilled artisan willappreciate that the blood level of ketone bodies, or a specific ketonebody, achieved may be a valuable measure of dosing frequency. Anyfrequency, regardless of whether expressly exemplified herein, thatallows maintenance of a blood level of the measured compound withinacceptable ranges can be considered useful herein. The skilled artisanwill appreciate that dosing frequency will be a function of thecomposition that is being consumed or administered, and somecompositions may require more or less frequent administration tomaintain a desired blood level of the measured compound (e.g., a ketonebody).

As used herein, the term “oral administration” or “orally administering”means that the mammal ingests, or a caretaker is directed to feed, ordoes feed, the mammal one or more of the compositions described herein.Wherein a human is directed to feed the composition, such direction maybe that which instructs and/or informs the human that use of thecomposition may and/or will provide the referenced benefit, for example,enhancing cognitive function, improving memory, improving liverfunction, improving learning, improving attention, improving socialbehavior, improving motor performance, and/or improving cerebrovascularfunction, or preventing, reducing, or delaying a decline in suchforegoing functions or qualities. Such direction may be oral direction(e.g., through oral instruction from, for example, a physician,veterinarian, or other health professional, or radio or television media(i.e., advertisement), or written direction (e.g., through writtendirection from, for example, a physician, veterinarian, or other healthprofessional (e.g., prescriptions), sales professional or organization(e.g., through, for example, marketing brochures, pamphlets, or otherinstructive paraphernalia), written media (e.g., internet, electronicmail, or other computer-related media), and/or packaging associated withthe composition (e.g., a label present on a container holding thecomposition).

The present invention provides a method of treating or preventingdiseases of reduced neuronal metabolism, including any age-associatedcognitive decline, such as AAMI, and the like, comprising administeringan effective amount of a composition comprising at least one compoundcapable of elevating ketone body concentrations in the body of a mammal(e.g., a patient), e.g., medium chain triglycerides, to a patient inneed thereof. Generally, an effective amount is an amount effective toeither (1) reduce the symptoms of the disease sought to be treated or(2) induce a change relevant to treating the disease sought to betreated. For any age-associated cognitive decline, such as AAMI, and thelike, an effective amount includes an amount effective to: increasecognitive scores; improve memory. As used herein, and discussedelsewhere herein, MCT of this invention are represented by the followingformula:

wherein R1, R2, and R3 are independently selected from the groupconsisting of a fatty acid residue esterified to a glycerol backbonehaving 5-12 carbons in the carbon backbone (C₅ to C₁₂ fatty acids), asaturated fatty acid residue esterified to a glycerol backbone having5-12 carbons in the carbon backbone (C₅ to C₁₂ fatty acids), anunsaturated fatty acid residue esterified to a glycerol backbone having5-12 carbons in the carbon backbone (C₅ to C₁₂ fatty acids), andderivatives of any of the foregoing. The structured lipids of thisinvention may be prepared by any process known in the art, such asdirect esterification, rearrangement, fractionation,transesterification, or the like. For example the lipids may be preparedby the rearrangement of a vegetable oil such as coconut oil.

In one embodiment, the method comprises the use of MCT wherein R1, R2,and R3 are fatty acids containing a six-carbon backbone (tri-C6:0).Tri-C6:0 MCT are absorbed very rapidly by the gastrointestinal tract ina number of animal model systems. The high rate of absorption results inrapid perfusion of the liver, and a potent ketogenic response. Inanother embodiment, the method comprises the use of MCT wherein R1, R2,and R3 are fatty acids containing an eight-carbon backbone (tri-C8:0).In another embodiment, the method comprises the use of MCT wherein R1,R2, and R3 are fatty acids containing a ten-carbon backbone (tri-C10:0).In another embodiment, the method comprises the use of MCT wherein R1,R2, and R3 are a mixture of C8:0 and C10:0 fatty acids. In anotherembodiment, the method comprises the use of MCT wherein R1, R2 and R3are a mixture of C6:0, C8:0, C10:0, and C12:0 fatty acids. In anotherembodiment, greater than 95% of R1, R2 and R3 carbon chains of the MCTare 8 carbons in length. In yet another embodiment, the R1, R2, and R3carbon chains are 6-carbon or 10-carbon chains. In another embodiment,50% of the R1, R2 and R3 carbon chains of the MCT are 8 carbons inlength and about 50% of the R1, R2 and R3 carbon chains of the MCT areabout 10 carbons in length. Additionally, utilization of MCT can beincreased by emulsification. Emulsification of lipids increases thesurface area for action by lipases, resulting in more rapid hydrolysisand release of MCFA. Methods for emulsification of these triglyceridesare well known to those skilled in the art.

In one embodiment, the method comprises the use of MCFA of 6, 8, 10 and12 carbon chain length or mixtures of the above.

In another embodiment, the invention comprises the co-administration ofa composition comprising at least one compound capable of elevatingketone body concentrations, such as, for example, emulsified MCT, andL-carnitine or a derivative of L-carnitine. Slight increases in MCFAoxidation have been noted when MCT are combined with L-carnitine (Odle,J., New insights into the utilization of medium-chain triglycerides bythe neonate: observations from a piglet model, J Nutr, 1997,127:1061-7). Thus in the present invention emulsified MCT are combinedwith L-carnitine at doses required to increase the utilization of saidMCT. The dosage of L-carnitine and MCT will vary according to thecondition of the host, method of delivery, and other factors known tothose skilled in the art, and will be of sufficient quantity to raiseblood ketone levels to a degree required to treat and prevent AAMI andthe like. Derivatives of L-carnitine which may be used in the presentinvention include but are not limited to decanoylcarnitine,hexanoylcarnitine, caproylcarnitine, lauroylcarnitine,octanoylcarnitine, stearoylcarnitine, myristoylcarnitine,acetyl-L-carnitine, O-Acetyl-L-carnitine, and palmitoyl-L-carnitine.

Therapeutically effective amounts of the therapeutic agents can be anyamount or dose sufficient to bring about the desired effect and depend,in part, on the severity and stage of the condition, the size andcondition of the patient, as well as other factors readily known tothose skilled in the art. The dosages can be given as a single dose, oras several doses, for example, divided over the course of several weeks,as discussed elsewhere herein.

In one embodiment, the ketogenic compounds are administered orally. Inanother embodiment, the ketogenic compounds are administeredintravenously. Oral administration of MCT and other ketogenic compoundpreparations of intravenous MCT and other ketogenic compound solutionsare well known to those skilled in the art.

In one embodiment, oral and/or intravenous administration of acomposition comprising at least one compound capable of elevating ketonebody concentrations, such as, for example, MCT or MCFA, result inhyperketonemia. Hyperketonemia, in one embodiment, results in ketonebodies being utilized for energy in the brain even in the presence ofglucose. Additionally, hyperketonemia results in a substantial (39%)increase in cerebral blood flow (Hasselbalch, S. G., et al., Changes incerebral blood flow and carbohydrate metabolism during acutehyperketonemia, Am J Physiol, 1996, 270:E746-51). Hyperketonemia hasbeen reported to reduce cognitive dysfunction associated with systemichypoglycemia in normal humans (Veneman, T., et al., Effect ofhyperketonemia and hyperlacticacidemia on symptoms, cognitivedysfunction, and counterregulatory hormone responses during hypoglycemiain normal humans, Diabetes, 1994, 43:1311-7). Please note that systemichypoglycemia is distinct from the local defects in glucose metabolismthat occur in any age-associated cognitive decline, such as AAMI, andthe like.

In all embodiments, the invention provides the subject compositionscomprising at least one compound that is capable of elevating ketonebody concentrations. Such compounds are also collectively referred to asketone body precursor compounds or ketogenic compounds. Such compoundsinclude compounds such as, for example, MCT, MCFA, and prodrugs,metabolic precursors, and so on, of ketone bodies. For example, in oneembodiment, the compound capable of elevating ketone body concentrationsin the body include one or more prodrugs, which can be metabolicallyconverted to the subject compounds by the recipient host. As usedherein, a prodrug is a compound that exhibits pharmacological activityafter undergoing a chemical transformation in the body. A prodrug canalso be referred to as a metabolic precursor if the conversion of theprodrug directly results in the formation of a ketone body. MCT and MCFAmust be first oxidized to acetyl-CoA, then undergo several steps beforebeing synthesized into ketone bodies. The class of ketone body precursorcompounds include, the compounds described hereinbelow. The ketone bodyprecursor compounds, in one embodiment, are administered in a dosagerequired to increase blood ketone bodies to a level required to treatand/or prevent the occurrence of any age-associated cognitive decline,such as AAMI, and the like. Appropriate dosages of all of thesecompounds can be determined by one of skill in the art.

A wide variety of prodrug formulations are known in the art. Forexample, prodrug bonds may be hydrolyzable, such as esters oranhydrides, or enzymatically biodegradable, such as amides.

Ketone body precursor compounds appropriate for the inventivecompositions of the present invention includes any compounds that arecapable of directly elevating ketone body concentrations in the body ofa mammal, e.g., a patient, and may be determined by one of skill in theart. These compounds can mimic the effect of increasing oxidation offatty acids and include but are not limited to the ketone bodies,D-β-hydroxybutyrate and acetoacetate, and metabolic precursors of these.The term metabolic precursor, used in this embodiment, can refer tocompounds that comprise 1,3butane diol, acetoacetyl orD-β-hydroxybutyrate moieties such as acetoacetyl-1-1,3-butane diol,acetoacetyl-D-β-hydroxybutyrate, and acetoacetylglycerol. Esters of anysuch compound with monohydric, dihydric or trihydric alcohols are alsoincluded in yet another embodiment. Metabolic precursors also includepolyesters of D-β-hydroxybutyrate, and acetoacetate esters ofD-β-hydroxybutyrate. Polyesters of D-β-hydroxybutyrate include oligomersof this polymer designed to be readily digestible and/or metabolized byhumans or mammals. These preferably are of 2 to 100 repeats long,typically 2 to 20 repeats long, and most conveniently from 3 to 10repeats long. Examples of poly D-β-hydroxybutyrate or terminallyoxidized poly-D-β-hydroxybutyrate esters useable as ketone bodyprecursors are given below:

In each case, n is selected such that the polymer or oligomer is readilymetabolized on administration to a human or mammal body to provideelevated ketone body levels in blood. Values of n are integers of 0 to1,000, more preferably 0 to 200, still more preferably 1 to 50, mostpreferably 1 to 20, particularly conveniently being from 3 to 5. In eachcase m is an integer of 1 or more, a complex thereof with one or morecations or a salt thereof for use in therapy or nutrition. Examples ofcations and typical physiological salts are described herein, andadditionally include sodium, potassium, magnesium, calcium, eachbalanced by a physiological counter-ion forming a salt complex,L-lysine, L-arginine, methyl glucamine, and others known to thoseskilled in the art.

Also included in the definition of a ketone body precursor compound areseveral other ketone body precursor compounds useful for treating ageassociated memory impairment; including esters of polyhydric alcohols,3-hydroxyacid esters and glycerol esters, as described more fullyhereinbelow. As used herein, “derivative” refers to a compound orportion of a compound that is derived from or is theoretically derivablefrom a parent compound; The term “hydroxyl group” is represented by theformula —OH; the term “alkoxy group” is represented by the formula —OR,where R can be an alkyl group, including a lower alkyl group, optionallysubstituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl,halogenated alkyl, or heterocycloalkyl group, as defined below; the term“ester” is represented by the formula —OC(O)R, where R can be an alkyl,alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, orheterocycloalkyl group, as defined below; the term “alkyl group” isdefined as a branched or unbranched saturated hydrocarbon group of 1 to24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl,hexadecyl, eicosyl, tetracosyl and the like. A “lower alkyl” group is asaturated branched or unbranched hydrocarbon having from 1 to 10 carbonatoms; the term “alkenyl group” is defined as a hydrocarbon group of 2to 24 carbon atoms and structural formula containing at least onecarbon-carbon double bond; the term “alkynyl group” is defined as ahydrocarbon group of 2 to 24 carbon atoms and a structural formulacontaining at least one carbon-carbon triple bond; the term “halogenatedalkyl group” is defined as an alkyl group as defined above with one ormore hydrogen atoms present on these groups substituted with a halogen(F, Cl, Br, I); the term “cycloalkyl group” is defined as a non-aromaticcarbon-based ring composed of at least three carbon atoms. Examples ofcycloalkyl groups include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, etc. The term “heterocycloalkylgroup” is a cycloalkyl group as defined above where at least one of thecarbon atoms of the ring is substituted with a heteroatom such as, butnot limited to, nitrogen, oxygen, sulfur, or phosphorous; the term“aliphatic group” is defined as including alkyl, alkenyl, alkynyl,halogenated alkyl and cycloalkyl groups as defined above. A “loweraliphatic group” is an aliphatic group that contains from 1 to 10 carbonatoms; the term “aryl group” is defined as any carbon-based aromaticgroup including, but not limited to, benzene, naphthalene, etc. The term“aromatic” also includes “heteroaryl group,” which is defined as anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorous. The aryl groupcan be substituted with one or more groups including, but not limitedto, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone,aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl group can beunsubstituted; the term “aralkyl” is defined as an aryl group having analkyl group, as defined above, attached to the aryl group. An example ofan aralkyl group is a benzyl group; “esterification” refers to thereaction of an alcohol with a carboxylic acid or a carboxylic acidderivative to give an ester; “transesterification” refers to thereaction of an ester with an alcohol to form a new ester compound. Theterm “3-hydroxybutyrate” is used interchangeably with the term“3-hydroxybutyric acid.”

In one embodiment, a compound capable of elevating ketone bodyconcentrations includes compounds according to formula:

wherein R is a polyhydric alcohol residue; n, m and x representintegers; and m is less than or equal to x.

Physiologically compatible alcohols suitable for forming esters with(R)-3-hydroxybutyrate and derivatives thereof include monohydric andpolyhydric alcohols. Esters of polyhydric alcohols deliver a higherdensity of (R)-3-hydroxybutyrate equivalents per equivalent of(R)-3-hydroxybutyrate derivative using shorter (R)-3-hydroxybutyrateoligomers. Shorter oligomers generally are more readily hydrolyzed togive elevated concentrations of (R)-3-hydroxybutyrate in blood. Examplesof polyhydric alcohols suitable for preparing such esters includecarbohydrates and carbohydrate derivatives, such as carbohydratealcohols, examples of carbohydrates include, without limitation,altrose, arabinose, dextrose, erythrose, fructose, galactose, glucose,gulose, idose, lactose, lyxose, mannose, ribose, sucrose, talose,threose, xylose and the like. Additional examples of carbohydratesuseful for preparing (R)-3-hydroxybutyrate derivatives include aminoderivatives, such as galactosamine, glucosamine and mannosamine,including N-acetyl derivatives, such as N-acetylglucosamine and thelike. Examples of carbohydrates also include carbohydrate derivatives,such as alkyl glycosides. Examples of carbohydrate alcohols include,without limitation, glycerol, mannitol, ribitol, sorbitol, threitol,xylitol and the like. The enantiomers of the above-listed carbohydratesand carbohydrate alcohols also can be used to prepare(R)-3-hydroxybutyrate derivatives according to the above formula.

Embodiments include compounds where n is from 1 to about 100; wherein xis from 1 to about 20; wherein m is from 1 to about 20. One embodimentincludes a compound wherein R is (R)-1,3-butanediol.

In another embodiment, compounds capable of elevating ketone bodyconcentrations include compounds of the formula

and also

where n and m independently are integers from 1 to about 100. In someembodiments, n and m are the same; n and m are different; and wherein nand m are 3.

In addition, compounds capable of elevating ketone body concentrationsinclude ester compounds of R-3-hydroxybutyrate according to the formula

wherein n is an integer from 1 to about 100. In one embodiment, n is 3.

Other compounds capable of elevating ketone body levels include3-hydroxyacids. The compositions include 3-hydroxyacids, linear orcyclic oligomers thereof, esters of the 3-hydroxyacids or oligomers,derivatives of 3-hydroxyacids, and combinations thereof. In oneembodiment, the compositions include the cyclic macrolide ofR-3-hydroxyacids containing 3, 4, or 5 monomeric subunits.3-hydroxyacids include 3-hydroxybutyric acid, 3-hydroxyvaleric acid,3-hydroxyhexanoic acid and 3-hydroxyheptanoic acid. In some embodiments,the length of the oligomer must be such that the derivative has asuitable digestion rate for sustained release of monomer. In anotherembodiment, the cyclic trimer (triolide) is used in a combination withother cyclic oligolides or linear esters and/or mixtures of both.

The general formula for 3-hydroxyacids is:

R₁ is selected from hydrogen, methyl, alkyl, alkenyl, aryl, arylalkyl,heteroalkyl, heteroaryl, thiol, disulfide, ether, thiol ether, amine,amide, halogen. R₂ and R₃ are independently selected from hydrogen,methyl, alkyl, alkenyl, aryl, arylalkyl, heteroalkyl, heteroaryl, thiol,disulfide, ether, thiol ether, amine, amide, halogen, hydroxy, ester,nitrogen-substituted radicals, and/or oxygen-substituted radicals. R₄ isselected from hydrogen, alkyl, alkenyl, aryl, arylalkyl, heteroalkyl,heteroaryl, thiol, disulfide, ether, thiol ether, amine, amide, halogen,hydroxy, ester, nitrogen-substituted radicals, and/or oxygen-substitutedradicals. Further, when R₄ is not hydrogen or a halogen, R₃ can be adirect bond to R₄ and R₄ can be methyl.

Other compounds capable of elevating ketone body levels include glycerolesters, namely, not readily water-soluble glycerides of at least oneketo or hydroxy acid, having the formula

wherein two or three of the groups R₁, R₂ and R₃ independently of eachother, are one or more of the groups acetoacetate, alpha-ketopropionate,beta-hydroxybutyrate and alpha-hydroxypropionate, and when only two ofthe groups R₁, R₂ and R₃ are any of said groups, the third of them is ahydroxy group or a residue of a saturated or unsaturated fatty acidcontaining 2 to 24 carbon atoms. Other glycerol esters are envisioned,particularly not readily water-soluble glycerides of at least one ketoor hydroxy acid, having the formula

wherein one R group is hydrogen, and two R groups are (—COCH₂, COCH₃).Additionally, wherein each R is the same or different and is hydrogen,or (—COCH₂, COCH₃), provided that at least one R is not hydrogen andwherein R′ is a linear acid ester of even carbon number from 2 to 20carbons.

This invention also provides the inventive compositions in oneembodiment in administratively convenient formulations including dosageunits incorporated into a variety of containers. Dosages of theinventive compositions, such as, for example, those comprising MCT, maybe administered in an effective in an effective amount to increase thecognitive ability of patients afflicted with diseases of reducedneuronal metabolism, such as in patients with any age-associatedcognitive decline, such as, AAMI, and the like.

In one embodiment, the inventive compositions result in elevating ketoneconcentrations in the body, and in this embodiment, the compositions areadministered in an amount that is effective to induce hyperketonemia. Inone embodiment, hyperketonemia results in ketone bodies being utilizedfor energy in the brain.

In one embodiment, the composition increases the circulatingconcentration of at least one type of ketone body in the mammal orpatient. In one embodiment, the circulating ketone body isD-beta-hydroxybutyrate. The amount of circulating ketone body can bemeasured at a number of times post administration, and in oneembodiment, is measured at a time predicted to be near the peakconcentration in the blood, but can also be measured before or after thepredicted peak blood concentration level. Measured amounts at theseoff-peak times are then optionally adjusted to reflect the predictedlevel at the predicted peak time. In one embodiment, the predicted peaktime is at about two hours. Peak circulating blood level and timing canvary depending on factors known to those of skill in the art, includingindividual digestive rates, co-ingestion or pre- or post-ingestion offoods, drinks, etc., as known to one of skill in the art. In oneembodiment, the peak blood level reached of D-beta-hydroxybutyrate isbetween about 0.05 millimolar (mM) to about 50 mM. Another way todetermine whether blood levels of D-beta-hydroxybutyrate are raised toabout 0.05 to about 50 mM is by measurement of D-beta-hydroxybutyrateurinary excretion a range in the range of about 5 mg/dL to about 160mg/dL. In other embodiments, the peak blood level is raised to about 0.1to about 40 mM, from about 0.1 to about 20 mM, from about 0.1 to about10 mM, to about 0.1 to about 5 mM, more preferably raised to about 0.15to about 2 mM, from about 0.15 to about 0.3 mM, although variations willnecessarily occur depending on the formulation and host, for example, asdiscussed above. In other embodiments, the peak blood level reached ofD-beta-hydroxybutyrate will be at least about 0.05 mM, at least about0.1 mM, at least about 0.15 mM, at least about 0.2 mM, at least about0.5 mM, at least about 1 mM, at least about 1.5 mM, at least about 2 mM,at least about 2.5 mM, at least about 3 mM, at least about 4 mM, atleast about 5 mM, at least about 10 mM, at least about 15 mM, at leastabout 20 mM, at least about 30 mM, at least about 40 mM, and at leastabout 50 mM.

Effective amount of dosages of compounds for the inventive compositions,i.e., compounds capable of elevating ketone body concentrations in anamount effective for the treatment of or prevention of loss of cognitivefunction caused by reduced neuronal function in AAMI will be apparent tothose skilled in the art. As discussed herein above, such effectiveamounts can be determined in light of disclosed blood ketone levels.Where the compound capable of elevating ketone body concentrations isMCT, the MCT dose, in one embodiment, is in the range of about 0.05g/kg/day to about 10 g/kg/day of MCT. In other embodiments, the dosewill be in the range of about 0.25 g/kg/day to about 5 g/kg/day of MCT.In other embodiments, the dose will be in the range of about 0.5g/kg/day to about 2 g/kg/day of MCT. In other embodiments, the dose willbe in the range of about 0.1 g/kg/day to about 2 g/kg/day. In otherembodiments, the dose of MCT is at least about 0.05 g/kg/day, at leastabout 0.1 g/kg/day, at least about 0.15 g/kg/day, at least about 0.2g/kg/day, at least about 0.5 g/kg/day, at least about 1 g/kg/day, atleast about 1.5 g/kg/day, at least about 2 g/kg/day, at least about 2.5g/kg/day, at least about 3 g/kg/day, at least about 4 g/kg/day, at leastabout 5 g/kg/day, at least about 10 g/kg/day, at least about 15g/kg/day, at least about 20 g/kg/day, at least about 30 g/kg/day, atleast about 40 g/kg/day, and at least about 50 g/kg/day.

Convenient unit dosage containers and/or formulations include tablets,capsules, lozenges, troches, hard candies, nutritional bars, nutritionaldrinks, metered sprays, creams, and suppositories, among others. Thecompositions may be combined with a pharmaceutically acceptableexcipient such as gelatin, oil(s), and/or other pharmaceutically activeagent(s). For example, the compositions may be advantageously combinedand/or used in combination with other therapeutic or prophylacticagents, different from the subject compounds. In many instances,administration in conjunction with the subject compositions enhances theefficacy of such agents. For example, the compounds may beadvantageously used in conjunction with antioxidants, compounds thatenhance the efficiency of glucose utilization, and mixtures thereof.

In one embodiment, the subject is intravenously infused with ketogeniccompounds such as MCT, MCFA, directly, to a level required to treat andprevent the occurrence of diseases of reduced neuronal metabolism, inpatients with any age-associated cognitive decline, such as AAMI, andthe like. Preparation of intravenous lipids and ketone body solutionsare well known to those skilled in the art.

In one embodiment, the invention provides a formulation comprising amixture of MCT and carnitine to provide elevated blood ketone levels.The nature of such formulations will depend on the duration and route ofadministration. Such formulations can be in the range of 0.05 g/kg/dayto 10 g/kg/day of MCT and 0.05 mg/kg/day to 10 mg/kg/day of carnitine orits derivatives. In one embodiment, an MCT dose can be in the range of0.05 g/kg/day to 10 g/kg/day of MCT. The dose can be in the range of0.25 g/kg/day to 5 g/kg/day of MCT. The dose can also be in the range of0.5 g/kg/day to 2 g/kg/day of MCT. In some embodiments, a carnitine orcarnitine derivative dose can be in the range of 0.05 mg/kg/day to 10mg/kg/day. The carnitine or carnitine derivative dose can be in therange of 0.1 mg/kg/day to 5 mg/kg/day. The carnitine or carnitinederivative dose can also be in the range of 0.5 mg/kg/day to 1mg/kg/day. Variations will necessarily occur depending on theformulation and/or host, for example.

In one embodiment, a formulation comprises a range of about 1 to about500 g of emulsified MCT combined with about 1 to about 2000 mg ofcarnitine. Amounts of MCT can be at least about 1 g, at least about 10g, at least about 50 g, at least about 100 g, at least about 150 g, atleast about 200 g, at least about 250 g, at least about 300 g, at leastabout 400 g. Amounts of carnitine can be at least about 1 g, at leastabout 50 g, at least about 100 g, at least about 250 g, at least about500 g, at least about 1000 g, at least about 1250 g, at least about 1500g. Another formulation comprises 50 g MCT (95% triC8:0) emulsified with50 g of mono- and di-glycerides combined with 500 mg of L-carnitine.Such a formulation is well tolerated and generally induceshyperketonemia for 3-4 hours in healthy human subjects.

The daily dose of MCT can be also be measured in terms of grams of MCTper kg of body weight (BW) of the mammal. The daily dose of MCT canrange from about 0.01 g/kg to about 10.0 g/kg BW of the mammal.Preferably, the daily dose of MCT is from about 0.1 g/kg to about 5 g/kgBW of the mammal. More preferably, the daily dose of MCT is from about0.2 g/kg to about 3 g/kg of the mammal. Still more preferably, the dailydose of MCT is from about 0.5 g/kg to about 2 g/kg of the mammal.

In some embodiments, the inventive compounds may be co administered withcarbohydrate, or be co-formulated with carbohydrate. Carbohydrate caninclude more than one type of carbohydrate. Appropriate carbohydratesare known in the art, and include simple sugars, such as glucose,fructose, sucrose, and the like. If co-formulated, the amount ofcarbohydrate to use can include at least about 0.1 g, at least about 1g, at least about 10 g, at least about 50 g, at least about 100 g, atleast about 150 g, at least about 200 g, at least about 250 g, at leastabout 300 g, at least about 400 g. Amounts of carnitine can be at leastabout 1 g, at least about 50 g, at least about 100 g.

In another embodiment, the methods of the present invention furthercomprise determination of the patients' genotype or particular alleles.In one embodiment, the patient's alleles of the apolipoprotein E geneare determined. In some examples, the inventor teaches that non-E4carriers performed better than those with the E4 allele when elevatedketone body levels were induced with MCT. Also, those with the E4 allelehad higher fasting ketone body levels and the levels continued to riseat the two hour time interval. Therefore, E4 carriers may require higherketone levels or agents that increase the ability to use the ketonebodies that are present. Accordingly, an embodiment consists of a doseof MCT combined with agents that increase the utilization of fats, MCTor ketone bodies. Examples of agents that increase utilization of fattyacids may be selected from a group comprising of, but not limited to,non-steroidal anti-inflammatory agents (NSAIDs), statin drugs (such asLipitor® and Zocor®) and fibrates. Examples of NSAIDs include: aspirin,ibuprofen (Advil, Nuprin, and others), ketoprofen (Orudis KT, Actron),and naproxen (Aleve).

NSAIDs function, in part, as PPAR-gamma agonists. Increasing PPAR-gammaactivity increases the expression of genes associated with fatty acidmetabolism such as FATP (for review, see (Gelman, L., et al., An updateon the mechanisms of action of the peroxisome proliferator-activatedreceptors (PPARs) and their roles in inflammation and cancer, Cell MolLife Sci, 1999, 55:932-43)). Accordingly, a combination of MCT andPPAR-gamma agonists will prove beneficial to patients with decreasedneuronal metabolism. In one embodiment the PPAR-gamma agonist is anNSAID.

Statins are a class of drugs with pleiotropic effects, the bestcharacterized being inhibition of the enzyme 3-hydroxy-3-methylglutarylCoA reductase, a key rate step in cholesterol synthesis. Statins alsohave other physiologic affects such as vasodilatory, anti-thrombotic,antioxidant, anti-proliferative, anti-inflammatory and plaquestabilizing properties. Additionally, statins cause a reduction incirculating triglyceride rich lipoproteins by increasing the levels oflipoprotein lipase while also decreasing apolipoprotein C-III (aninhibitor of lipoprotein lipase) (Schoonjans, K., et al.,3-Hydroxy-3-methylglutaryl CoA reductase inhibitors reduce serumtriglyceride levels through modulation of apolipoprotein C-III andlipoprotein lipase, FEBS Lett, 1999, 452:160-4). Accordingly,administration of statins results in increased fatty acid usage, whichcan act synergistically with MCT administration. This should proveespecially beneficial to ApoE4 carriers. One embodiment of thisinvention would be combination therapy consisting of statins and MCT.

Fibrates, such as Bezafibrate, ciprofibrate, fenofibrate andGemfibrozil, are a class of lipid lowering drugs. They act as PPAR-alphaagonists and similar to statins they increase lipoprotein lipase, apoAIand apoAII transcription and reduce levels of apoCIII (Staels, B., etal., Mechanism of action of fibrates on lipid and lipoproteinmetabolism, Circulation, 1998, 98:2088-93). As such they have a majorimpact on levels of triglyceride rich lipoproteins in the plasma,presumably by increasing the use of fatty acids by peripheral tissues.Accordingly, the present invention discloses that fibrates alone or incombination with MCT would prove beneficial to patients with reducedneuronal metabolism such as those with any age-associated cognitivedecline, such as AAMI and the like.

Caffeine and ephedra alkaloids are commonly used in over the counterdietary supplements. Ephedra alkaloids are commonly derived from plantsources such as ma-huang (Ephedra sinica). The combination of caffeineand ephedra stimulate the use of fat. Ephedra alkaloids are similar instructure to adrenaline and activate beta-adenergic receptors on cellsurfaces. These adenergic receptors signal through cyclic AMP (cAMP) toincrease the use of fatty acids. cAMP is normally degraded byphosphodiesterase activity. One of the functions of caffeine is toinhibit phosphodiesterase activity and thereby increase cAMP mediatedsignaling. Therefore caffeine potentiates the activity of the ephedraalkaloids. Accordingly, the present invention discloses that ephedraalkaloids alone can provide a treatment or prevention for conditions ofreduced neuronal metabolism. Additionally, it is disclosed that ephedraalkaloids in combination with caffeine can provide a treatment orprevention for conditions of reduced neuronal metabolism. Accordingly,it is disclosed that a combination of MCT with ephedra, or MCT withcaffeine, or MCT, ephedra alkaloids and caffeine together can provide atreatment or prevention for diseases of reduced neuronal metabolism, inpatients with any age-associated cognitive decline, such as AAMI, andthe like.

Ketone bodies are used by neurons as a source of Acetyl-CoA. Acetyl-CoAis combined with oxaloacetate to form citrate in the Krebs' cycle, orcitric acid cycle (TCA cycle). It is important for neurons to have asource of Acetyl-CoA as well as TCA cycle intermediates to maintainefficient energy metabolism. Yet, neurons lose TCA cycle intermediatesto synthesis reactions, such as the formation of glutamate. Neurons alsolack pyruvate carboxylase and malic enzyme so they cannot replenish TCAcycle intermediates from pyruvate (Hertz, L., et al.,Neuronal-astrocytic and cytosolic-mitochondrial metabolite traffickingduring brain activation, hyperammonemia and energy deprivation,Neurochem Int, 2000, 37:83-102). Accordingly, the present inventiondiscloses that a combination of ketone bodies with a source of TCA cycleintermediates, in one embodiment. TCA cycle intermediates are selectedfrom a group consisting of citric acid, aconitic acid, isocitric acid,α-ketoglutaric acid, succinic acid, fumaric acid, malic acid,oxaloacetic acid, and mixtures thereof. One embodiment of the inventionis a combination of TCA cycle intermediates with MCT in a formulation toincrease efficiency of the TCA.

Another source of TCA cycle intermediates are compounds that areconverted to TCA cycle intermediates within the body (TCA intermediateprecursors). Examples of such compounds are 2-keto-4-hydroxypropanol,2,4-dihydroxybutanol, 2-keto-4-hydroxybutanol, 2,4-dihydroxybutyricacid, 2-keto-4-hydroxybutyric acid, aspartates as well as mono- anddi-alkyl oxaloacetates, pyruvate and glucose-6-phosphate. Accordingly,the present invention discloses that a combination of TCA intermediateprecursors with ketone bodies will be beneficial for the treatment andprevention of diseases resulting from reduced metabolism. Also, thepresent invention discloses that MCT combined with TCA intermediateprecursors will be beneficial for the treatment and prevention ofdiseases resulting from reduced metabolism.

The present invention further discloses that additional sources of TCAcycle intermediates and Acetyl-CoA can be advantageously combined withketone body therapy. Sources of TCA cycle intermediates and Acetyl-CoAinclude mono- and di-saccharides as well as triglycerides of variouschain lengths and structures.

Further benefit can be derived from formulation of a pharmaceuticalcomposition that includes metabolic adjuvants. Metabolic adjuvantsinclude vitamins, minerals, antioxidants and other related compounds.Such compounds may be chosen from a list that includes but is notlimited to; ascorbic acid, biotin, calcitriol, cobalamin, folic acid,niacin, pantothenic acid, pyridoxine, retinol, retinal (retinaldehyde),retinoic acid, riboflavin, thiamin, a-tocopherol, phytylmenaquinone,multiprenylmenaquinone, calcium, magnesium, sodium, aluminum, zinc,potassium, chromium, vanadium, selenium, phosphorous, manganese, iron,fluorine, copper, cobalt, molybdenum, iodine. Accordingly a combinationof ingredients chosen from: metabolic adjuvants, compounds that increaseketone body levels, and TCA cycle intermediates, will prove beneficialfor treatment and prevention of diseases of reduced neuronal metabolism,in patients with any age-associated cognitive decline, such as AAMI, andthe like.

Administration of compositions comprising at least one compound capableof elevating ketone body concentrations, such as MCT, includingtriglycerides composed of C6 and C8 fatty acid residues, can result inelevated ketone body levels even if large amounts of carbohydrate areconsumed at the same time (for overview see (Odle, J., New insights intothe utilization of medium-chain triglycerides by the neonate:observations from a piglet model, J Nutr, 1997, 127:1061-7); see alsocopending United States Patent Provisional Patent Application Ser. No.60/323,995, “Drug Targets for Alzheimer's Disease and Other DiseasesAssociated with Decreased Neuronal Metabolism,” filed Sep. 21, 2001).The advantages of the Applicant's approach are clear, since carefulmonitoring of what is eaten is not required and compliance is muchsimpler.

Further benefit can be derived from formulation of a pharmaceuticalcomposition comprising a composition comprising at least one compoundcapable of elevating ketone body concentrations in the mammal with othertherapeutic agents in patients with any age-associated cognitivedecline, such as AAMI, and the like. Such therapeutic agents includeacetylcholinesterase inhibitors, acetylcholine synthesis modulators,acetylcholine storage modulators, acetylcholine release modulators,anti-inflammatory agents, estrogen or estrogen derivatives, insulinsensitizing agents, β-amyloid plaque removal agents (includingvaccines), inhibitors of β-amyloid plaque formation, γ-secretasemodulators, pyruvate dehydrogenase complex modulators, neurotrophicgrowth factors (e.g., BDNF), ceramides or ceramide analogs, and/or NMDAglutamate receptor antagonists (for overview of such treatments, see(Selkoe, D. J., Alzheimer's disease: genes, proteins, and therapy,Physiol Rev, 2001, 81:741-66) (Bullock, R., New drugs for Alzheimer'sdisease and other dementias, Br J Psychiatry, 2002, 180:135-9)). Whilesuch treatments are still in the experimental stage it is the novelinsight of the present invention that said treatments be advantageouslycombined with increased fatty acid/ketone body usage as describedherein.

From the description above, a number of advantages of the invention fortreating and preventing diseases of reduced neuronal metabolism, inpatients with any age-associated cognitive decline, such as AAMI, andthe like, become evident:

(a) Current treatments for diseases of reduced neuronal metabolism, inpatients with any age-associated cognitive decline, such as AAMI, andthe like, are merely palliative and do not address the reduced neuronalmetabolism associated with these conditions. Ingestion of the inventivecompositions as a nutritional supplement is a simple method to provideneuronal cells, in which glucose metabolism is compromised, with ketonebodies as a metabolic substrate.

(b) Increased blood levels of ketone bodies can be achieved by acomposition or regimen rich in ketogenic compositions such as mediumchain triglycerides.

(c) Many ketogenic compounds, such as medium chain triglycerides, can beinfused intravenously into patients or administered orally.

(d) Levels of ketone bodies can be easily measured in urine or blood bycommercially available products (e.g., Ketostix®, Bayer, Inc.).

According to the invention, disclosed is use of ketogenic compounds,such as MCT or MCFA, as a treatment and preventative measure of diseasesof reduced neuronal metabolism, in patients with any age-associatedcognitive decline, such as AAMI, and the like, which provides a novelmeans of alleviating reduced neuronal metabolism associated with theseconditions. It is the novel and significant insight of the presentinvention that use of ketogenic compounds such as MCT and MCFA resultsin hyperketonemia which will provide increased neuronal metabolism fordiseases of reduced neuronal metabolism in patients with anyage-associated cognitive decline, such as AAMI, and the like. Althoughthe description above contains much specificity, these should not beconstrued as limiting the scope of the invention but merely as providingillustrations for some of the embodiments of this invention. Forexample, supplementation with ketogenic compounds such as MCT may provemore effective when combined with insulin sensitizing agents such asvanadyl sulfate, chromium picolinate, and vitamin E. Such agents mayfunction to increase glucose utilization in compromised neurons and worksynergistically with hyperketonemia. In another example ketogeniccompounds such as MCT can be combined with compounds that increase therates of fatty acid utilization such as L-carnitine and its derivatives.Mixtures of such compounds may synergistically increase levels ofcirculating ketone bodies.

In some embodiments, the mammal is specifically a human. Other mammalswithin the scope of this invention are mammals such as companionanimals, such as a pet or mammal in the care of a human for whether fora long term or briefly. In some embodiments, the companion mammal is adog or cat.

In one embodiment, the mammal is a healthy aging mammal, as definedherein above. In such embodiments, the mammal will not be known to haveovert signs or substantial symptoms or indicia of cognitive impairment,as determined by a skilled artisan. Although the mammal may have otherhealth issues, even age-related health issues, they will be of suchcharacter as to not substantially impact the cognitive, motor, orbehavioral functioning of the mammal. Thus, the skilled artisan willappreciate that it may be impossible to classify an aging or geriatricmammal as completely “healthy”—it is not necessary to do so to practicethe methods and compositions provided herein. In other embodiments, theaging mammal is specifically understood to have age-related cognitiveimpairment, whether determined by formal diagnosis, or by its evidencinghallmarks of cognitive, memory, or motor impairments or behavioralindicia of such impairment or the like. In one embodiment, the mammalhas a characteristic or phenotype associated with age-related cognitiveimpairment, for example the mammal has one or more of the followingcharacteristic or phenotypic expressions of cognitive, motor, orbehavioral difficulties associated with age. For example, decreasedability to recall, short-term memory loss, decreased learning rate,decreased capacity for learning, decreased problem solving skills,decreased attention span, decreased motor performance, increasedconfusion, or dementia, as compared to a control mammal not having thephenotype.

In one embodiment, the compositions of the invention are foodcompositions, such as pet foods. In certain embodiments, the compositionis a food composition, further comprising in addition to the MCT, about15-50% protein, 5-40% fat, 5-40% carbohydrate, each on a dry weightbasis, and having a moisture content of 5-20%. In certain embodiments,the foods are intended to supply complete necessary dietaryrequirements. Also provided are compositions that are useful as snacks,nutrition bars, or other forms of food products or nutritional ordietary supplements, including tablets, capsules, gels, pastes,emulsions, caplets, and the like as discussed below. Optionally, thefood compositions can be a dry composition, semi-moist composition, wetcomposition, or any mixture thereof.

In another embodiment, the compositions of the invention are foodproducts formulated specifically for human consumption. These willinclude foods and nutrients intended to supply necessary dietaryrequirements of a human being as well as other human dietarysupplements. In a one embodiment, the food products formulated for humanconsumption are complete and nutritionally balanced, while in othersthey are intended as nutritional supplements to be used in connectionwith a well-balanced or formulated diet.

In another embodiment, the composition is a food supplement, such asdrinking water, beverage, liquid concentrate, gel, yogurt, powder,granule, paste, suspension, chew, morsel, treat, snack, pellet, pill,capsule, tablet, or any other delivery form. The nutritional supplementscan be specially formulated for consumption by a particular species oreven an individual mammal, such as companion mammal, or a human. In oneembodiment, the nutritional supplement can comprise a relativelyconcentrated dose of MCT such that the supplement can be administered tothe mammal in small amounts, or can be diluted before administration toa mammal. In some embodiments, the nutritional supplement or otherMCT-containing composition may require admixing with water or the likeprior to administration to the mammal, for example to adjust the dose,to make it more palatable, or to allow for more frequent administrationin smaller doses.

The MCT-containing compositions may be refrigerated or frozen. The MCTmay be pre-blended with the other components of the composition toprovide the beneficial amounts needed, may be emulsified, coated onto apet food composition, nutritional or dietary supplement, or food productformulated for human consumption, or may be added to a composition priorto consuming it or offering it to a mammal, for example, using a powderor a mix.

In one embodiment, the compositions comprise MCT in an amount effectiveto enhance cognitive function and behavior in a mammal to which thecomposition has been administered. For formulations formulated for humanconsumption, the amount of MCT as a percentage of the composition is inthe range of about 1% to about 50% of the composition on a dry matterbasis, although a lesser or greater percentage can be supplied. Invarious embodiments, the amount is about 1.0%, 1.5%, 2.0%, 2.5%, 3.0%,3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%,10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%,16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, 20%, 20.5%, 21%, 21.5%,22%, 22.5%, 23%, 23.5%, 24%, 24.5%, 25%, 25.5%, 26%, 26.5%, 27%, 27.5%,28%, 28.5%, 29%, 29.5%. 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50% or more, ofthe composition on a dry weight basis. Nutritional supplements may beformulated to contain several fold higher concentrations of MCT, to beamenable for administration to a mammal in the form of a tablet,capsule, liquid concentrated, or other similar dosage form, or to bediluted before administrations, such as by dilution in water, sprayingor sprinkling onto a pet food, and other similar modes ofadministration. For a nutritional or dietary supplement, MCT alone maybe administered directly to the mammal or applied directly to themammal's regular food. Nutritional or dietary supplement formulations invarious embodiments contain about 30% to about 100% MCT, although lesseramounts may also used.

Sources of the MCT include any suitable source, semi-synthetic,synthetic or natural. Examples of natural sources of MCT include plantsources such as coconuts and coconut oil, palm kernels and palm kerneloils, and animal sources such as milk from any of a variety of species,e.g., goats.

In various embodiments, the compositions optionally comprisesupplementary substances such as minerals, vitamins, salts, condiments,colorants, and preservatives. Non-limiting examples of supplementaryminerals include calcium, phosphorous, potassium, sodium, iron,chloride, boron, copper, zinc, magnesium, manganese, iodine, selenium,and the like. Non-limiting examples of supplementary vitamins includevitamin A, any of the B vitamins, vitamin C, vitamin D, vitamin E, andvitamin K, including various salts, esters, or other derivatives of theforegoing. Additional dietary supplements may also be included, forexample, any form of niacin, pantothenic acid, inulin, folic acid,biotin, amino acids, and the like, as well as salts and derivativesthereof. In addition, the compositions may comprise beneficial longchain polyunsaturated fatty acids such as the (n−3) and/or (n−6) fattyacids, arachidonic acid, eicosapentaenoic acid, docosapentaenoic acid,and docosahexaenoic acid, as well combinations thereof.

The compositions provided herein optionally comprise one or moresupplementary substances that promote or sustain general neurologichealth, or further enhance cognitive function. Such substances include,for example, choline, phosphatidylserine, alpha-lipoic acid, CoQ10,acetyl-L-carnitine, and herbal extracts such as Gingko biloba, Bacopamonniera, Convolvulus pluricaulis, and Leucojum aestivum.

In various embodiments, the pet food or dietary supplement compositionsprovided herein preferably comprise, on a dry weight basis, from about15% to about 50% crude protein. The crude protein material comprise oneor more proteins from any source whether animal, plant, or other. Forexample, vegetable proteins such as soybean, cottonseed, and peanut aresuitable for use herein Animal proteins such as casein, albumin, andmeat protein, including pork, lamb, equine, poultry, fish, or mixturesthereof are useful.

The compositions may further comprise, on a dry weight basis, from about5% to about 40% fat. The compositions may further comprise a source ofcarbohydrate. The compositions typically comprise from about 15% toabout 40% carbohydrate, on a dry weight basis. Examples of suchcarbohydrates include grains or cereals such as rice, corn, sorghum,alfalfa, barley, soybeans, canola, oats, wheat, or mixtures thereof. Thecompositions also optionally comprise other components that comprisecarbohydrates such as dried whey and other dairy products orby-products.

In certain embodiments, the compositions also comprise at least onefiber source. Any of a variety of soluble or insoluble fibers suitablefor use in foods or feeds may be utilized, and such will be known tothose of ordinary skill in the art. Presently included fiber sourcesinclude beet pulp (from sugar beet), gum arabic, gum talha, psyllium,rice bran, carob bean gum, citrus pulp, pectin, fructooligosaccharideadditional to the short chain oligofructose, mannanoligofructose, soyfiber, arabinogalactan, galactooligosaccharide, arabinoxylan, ormixtures thereof. Alternatively, the fiber source can be a fermentablefiber. Fermentable fiber has previously been described to provide abenefit to the immune system of a companion animal. Fermentable fiber orother compositions known to those of skill in the art which provide aprebiotic composition to enhance the growth of probiotic microorganismswithin the intestine may also be incorporated into the composition toaid in the enhancement of the benefit provided by the present inventionto the immune system of an mammal. Additionally, probioticmicroorganisms, such as Lactobacillus or Bifidobacterium species, forexample, may be added to the composition. The skilled artisan willunderstand how to determine the appropriate amount of MCT to be added toa given composition. Such factors that may be taken into account includethe type of composition (e.g., food composition, drink, dietarysupplement, or food product formulated for human consumption), theaverage consumption of specific types of compositions by differentmammals, the intended or required dose of MCT, the palatability andacceptability of the final product for the intended recipient orconsumer, the manufacturing conditions under which the composition isprepared, the convenience for the purchaser, and packagingconsiderations. Preferably, the concentrations of MCT to be added to thecomposition are calculated on the basis of the energy and nutrientrequirements of the mammal. The MCT can be added at any time during themanufacture and/or processing of the composition whether as part of aformulation of a pet food composition, dietary supplement, or foodproduct for human consumption, or as a coating or additive to any of theforegoing.

The present invention also relates to a method for treatment of agerelated cognitive decline or AAMI, comprising the steps of identifying apopulation of healthy aging mammals having AAMI, dividing the populationinto at least a control group and one or more test groups, formulatingat least one delivery system for delivering a composition comprising atleast one compound capable of elevating ketone body concentrations in anamount effective for elevating at least one type of ketone body in theblood of an individual mammal, wherein, on an extended regular basis,each test group receives a formulation delivering a compositioncomprising at least one compound capable of elevating ketone bodyconcentrations in an amount effective for elevating at least one type ofketone body in the blood of an individual mammal and the control groupdoes not receive any composition comprising at least one compoundcapable of elevating ketone body concentrations in an amount effectivefor elevating at least one type of ketone body in the blood of anindividual mammal. The method further comprises comparing at least oneneuropsychological test result in the control and test groups,determining which of the delivery systems for delivering the compositioncomprising at least one compound capable of elevating ketone bodyconcentrations in an amount effective for elevating at least one type ofketone body in the blood of an individual mammal was effective inimproving the results of at least one neuropsychological test; andadministering a treatment-based delivery system determined in theprevious step to a population of aging mammals, thereby treating AAMI.

EXAMPLES

The following examples are provided for illustrative purposes only andare not intended to limit the scope of the invention.

Example 1 Nutritional Drink

Nutritional drinks are prepared comprising the following ingredients:emulsified MCT in the range of 5 to 100 g/drink, L-carnitine in therange of 0.1 to lgram/drink, mix of vitamins and minerals at recommendeddaily levels, and a variety of flavorings.

Example 2 Additional Formulations

Additional formulations can be in the form of Ready to Drink Beverages,Powdered Beverages, Nutritional Drinks, Food Bars, Puddings, otherconfections and the like. Formulations for such are clear to thoseskilled in the art.

A. Ready to Drink Beverage Ready to Drink Beverages are prepared so asto comprise the following ingredients: emulsified MCT in the range of5-100 g/drink, L-carnitine in the range of 100-1000 mg/drink, and avariety of flavorings and other ingredients used to increasedpalatability, stability, etc.

B. Powdered Beverages MCT may be prepared in a dried form, useful forfood bars and powdered beverage preparations. A powdered beverage may beprepared so as to comprise the following components per drink: driedemulsified MCT in the range of 10-50 g, L-carnitine in the range of250-500 mg, sucrose in the range of 8-15 g, maltodextrin in the range of1-5 g, flavorings 0-1 g and other ingredients used to increasedpalatability, stability, etc.

C. Food Bar A food bar would be comprised of: dried emulsified MCT0.1-50 g, L-carnitine 250-500 mg, glycerin 1-5 g, corn syrup solids 5-25g, cocoa 2-7 g, coating 15-25 g.

D. Gelatin Capsules Hard or soft gelatin capsules are prepared using thefollowing ingredients: MCT 0.1-1000 mg/capsule, L-carnitine 250-500mg/capsule, Starch, NF 0-600 mg/capsule; Starch flowable powder 0-600mg/capsule; Silicone fluid 350 centistokes 0-20 mg/capsule. Theingredients are mixed, passed through a sieve, and filled into capsules.

E. Tablets Tablets are prepared so as to comprise the followingingredients: MCT 0.1-1000 mg/tablet; L-carnitine 250-500 mg/tablet;Microcrystalline cellulose 20-300 mg/tablet; Starch 0-50 mg/tablet;Magnesium stearate or stearate acid 0-15 mg/tablet; Silicon dioxide,fumed 0-400 mg/tablet; silicon dioxide, colloidal 0-1 mg/tablet, andlactose 0-100 mg/tablet. The ingredients are blended and compressed toform tablets.

F. Suspensions Suspensions are prepared so as to comprise the followingingredients: 0.1-1000 mg MCT; 250-500 mg L-carnitine; Sodiumcarboxymethyl cellulose 50-700 mg/5 ml; Sodium benzoate 0-10 mg/5 ml;Purified water 5 ml; and flavor and color agents as needed.

G. Parenteral Solutions A parenteral composition is prepared by stirringso as to comprise 1.5% by weight of MCT and L-carnitine in 10% by volumepropylene glycol and water. The solution is made isotonic with sodiumchloride and sterilized.

Example 3 Improvement in Cognitive Function in an Elderly Populationwith Treatment with Medium Chain Triglycerides

The study recruited four elderly subjects, two males and two females.Average age was 54.24 years. All subjects were free from any significantmedical, neurological, or psychiatric illness. Subjects were taking nocentral nervous system medications. Subjects were asked to fastovernight for approximately 12 hours on the night prior to the studyvisit. They arrived in the morning and baseline measurements were takenon three tests: a measure of simple reaction time, a memory scanningparadigm and a mental rotation task. Each test included a set ofpractice measurements which were not recorded. The practice tests aredesigned to minimize practice effects of repeated testing. The subjectsthen consumed the test article, waited 1 hour and then all three testswere repeated.

Test Article.

The test article comprised 20 grams of a 50% medium chaintriglyceride/50% corn starch powder mixed with Ensure™. The test articledelivered a total of 10 grams of medium chain triglycerides. Thesubjects were asked to consume the test article in 10 minutes or less.

Reaction Time.

The reaction time test measured reaction to a stimulus presented on acomputer screen. The subject's task was to press the Z key if thestimulus appeared on the left portion of the screen and the / key if thestimulus appeared on the right side of the screen. Reaction time wasmeasured in milliseconds. If the response was incorrect or greater than1500 milliseconds then the default value of 1500 ms was assigned. Eachsession comprised 9 blocks of 50 measurements. The first 3 blocks werepractice blocks that were not recorded and meant to minimize practiceeffects in the test. Therefore, 6 blocks of 50 measurements each wererecorded per session for a total of 300 individual measurements.

Memory Scanning.

The memory scanning task measured the ability of the subject to brieflyhold a set of numbers in short term memory. The subject is presentedwith a set of digits “to be remembered”. The number of digits variedbetween 1 to 6 digits. After a brief delay of 500 ms the subject wasthen presented with a “probe” digit. The subject's task was to rememberif the probe digit was present in the “to be remembered” set of digits.If the probe digit was included in the “to be remembered” set, thensubject pressed the / key on the keyboard. If the probe digit was not inthe “to be remembered set”, the subject pressed the Z key. Both correctanswers and the time it takes to respond were recorded. Each sessioncomprised of 6 blocks of 48 trials. The first block was a practice blockwas not recorded and meant to minimize practice effects in the test.Therefore, 5 blocks of 48 measurements were recorded per session for atotal of 240 individual measurements.

Mental Rotation.

The mental rotation task measured how quickly the subjects couldmentally rotate an object. On each trial, the subject was presented witha symbol resembling an upper-case ‘F’. The symbol was presented at oneof eight orientations, and was either a letter ‘F’ or the mirror-imageof an ‘F’. The subject's task was to determine whether the symbol was anormal or a reversed ‘F’, and to respond as quickly as possible bypushing the Z key if the symbol was reversed, or the / key if the symbolwas not reversed. If the response was incorrect, or if an invalid keywas pressed, a brief tone was heard and the maximum time (1500 ms) wasassigned to that incorrect value. Each session comprised 5 blocks of 16trials. The first block was a practice block and was not recorded andmeant to minimize practice effects in the test. Therefore, 4 blocks of16 measurements were recorded per session for a total of 64 individualmeasurements.

Results.

Results were analyzed by t-test comparing mean response times betweenBaseline and Treatment sessions. Administration of medium chaintriglyceride resulted in significant improvement in the Memory Scanningtask (p<0.0001) as well as the Mental Rotation task (p 0.0497). Nosignificant change was found in simple reaction time. See Table 1.

TABLE 1 Test Baseline Mean (ms) Test Mean (ms) P-value Reaction Time536.332 510.730 0.1564 Memory Scanning 841.127 743.576 <0.0001 MentalRotation 896.654 863.626 0.0497

For the Memory Scanning task, subjects improved in performance withfaster reaction time regardless of the set size to be remembered (seeFIG. 1).

FIG. 1 shows that 10 grams of medium chain triglycerides improvesperformance on a Memory Scanning task. Solid squares and solid linerepresent Baseline response times. Open circles and dashed linesrepresent Treatment response times. Error bars represent standard errorof the mean. * represent p<0.05 for individual set sizes.

At each set size the MCT supplemented drink statistically improvedperformance (see Table 2) as shown in FIG. 1.

TABLE 2 Mem Scan Set Size Baseline Mean Test Mean P-value n 1 642.938537.938 <0.0001 320 2 758.931 676.469 0.0004 320 3 847.769 747.413<0.0001 320 4 889.638 771.612 <0.0001 320 5 938.769 829.7 0.001 320 6968.950 898.325 0.0267 320

Example 4 Improvement in Cognitive Function in an Elderly Populationwith Medium Chain Triglycerides and L-Carnitine

The study recruited three elderly subjects, two males and one female.Average age was 57 years. All subjects were free from any significantmedical, neurological, or psychiatric illness. Subjects were taking nocentral nervous system medications. Subjects were asked to fastovernight for approximately 12 hours on the night prior to the studyvisit. They arrived in the morning and baseline measurements were takenon three tests: a measure of simple reaction time, a memory scanningparadigm and a mental rotation task. Each test included a set ofpractice measurements which were not recorded. The practice tests aredesigned to minimize practice effects of repeated testing. The subjectsthen consumed the test article, waited 1 hour and then all three testswere repeated. The task was designed to test if mixtures of medium chaintriglycerides with L-carnitine could improve cognitive performance in anelderly population.

Test Article.

The test article comprised 10 grams of a 50% medium chaintriglyceride/50% corn starch powder and 250 mg of L-carnitine mixed withEnsure™. The test article delivered a total of 5 grams of medium chaintriglycerides with 250 mg of L-carnitine. The subjects were asked toconsume the test article in 10 minutes or less.

Reaction Time.

The reaction time test measured reaction to a stimulus presented on acomputer screen. The subject's task was to press the Z key if thestimulus appeared on the left portion of the screen and the / key if thestimulus appeared on the right side of the screen. Reaction time wasmeasured in milliseconds. If the response was incorrect or greater than1500 milliseconds then the default value of 1500 ms was assigned. Eachsession comprised 9 blocks of 50 measurements. The first 3 blocks werepractice blocks that were not recorded and meant to minimize practiceeffects in the test. Therefore, 6 blocks of 50 measurements each wererecorded per session for a total of 300 individual measurements.

Memory Scanning.

The memory scanning task measured the ability of the subject to brieflyhold a set of numbers in short term memory. The subject is presentedwith a set of digits “to be remembered”. The number of digits variedbetween 1 to 6 digits. After a brief delay of 500 ms the subject wasthen presented with a “probe” digit. The subject's task was to rememberif the probe digit was present in the “to be remembered” set of digits.If the probe digit was included in the “to be remembered” set, thensubject pressed the / key on the keyboard. If the probe digit was not inthe “to be remembered set”, the subject pressed the Z key. Both correctanswers and the time it takes to respond were recorded. Each sessioncomprised of 6 blocks of 48 trials. The first block was a practice blockwas not recorded and meant to minimize practice effects in the test.Therefore, 5 blocks of 48 measurements were recorded per session for atotal of 240 individual measurements.

Mental Rotation.

The mental rotation task measured how quickly the subjects couldmentally rotate an object. On each trial, the subject was presented witha symbol resembling an upper-case ‘F’. The symbol was presented at oneof eight orientations, and was either a letter ‘F’ or the mirror-imageof an ‘F’. The subject's task was to determine whether the symbol was anormal or a reversed ‘F’, and to respond as quickly as possible bypushing the Z key if the symbol was reversed, or the / key if the symbolwas not reversed. If the response was incorrect, or if an invalid keywas pressed, a brief tone was heard and the maximum time (1500 ms) wasassigned to that incorrect value. Each session comprised 5 blocks of 16trials. The first block was a practice block and was not recorded andmeant to minimize practice effects in the test. Therefore, 4 blocks of16 measurements were recorded per session for a total of 64 individualmeasurements.

Results.

Results were analyzed by t-test comparing mean response times betweenBaseline and Treatment sessions. Administration of medium chaintriglyceride resulted in significant improvement in the Memory Scanningtask (p<0.0001) as well as the Mental Rotation task (p<0.0001). Nosignificant change was found in simple reaction time. See Table 3.

TABLE 3 Test Baseline Mean (ms) Test Mean (ms) P-value Reaction Time531.990 504.874 0.1955 Memory Scanning 792.529 692.958 <0.0001 MentalRotation 873.724 796.592 <0.0001

For the Memory Scanning task, MCT+carnitine improved performance withfaster reaction time regardless of the set size to be remembered (seeFIG. 2).

FIG. 2 shows that 10 grams of medium chain triglycerides with 250 mg ofL-carnitine improves performance on a Memory Scanning task. Solidsquares and solid line represent Baseline response times. Open circlesand dashed lines represent Treatment response times. Error barsrepresent standard error of the mean. * represent p<0.05 for individualset sizes. At each set size MCT supplemented drink statisticallyimproved performance (see Table 4) as shown in FIG. 2.

TABLE 4 Mem Scan Set Size Baseline Mean Test Mean P-value N 1 539.587541.237 0.9453 80 2 708.075 589.663 <0.0001 80 3 777.125 660.55 <0.000180 4 845.362 737.25 0.0055 80 5 910.337 772.725 0.0007 80 6 974.688856.325 0.0098 80

Example 5 Improvement in Cognitive Function in Subjects Diagnosed withAge Associated Memory Impairment (AAMI) Treated with Medium ChainTriglycerides

A randomized, double-blind, placebo-controlled, parallel group,multi-center design study of a medium chain triglyceride (Ketasyn™) forAge Associated Memory Impairment was conducted.

Study Overview.

159 outpatients diagnosed as having AAMI were enrolled in the study.Sixty-two (62) male and ninety-seven (97) female subjects between ages50 and 85 were enrolled. Mean age was 65 years of age.

Study Screening Measures.

The following tests and rating scales were used as screening measures toselect subjects with AAMI and to exclude subjects with dementia or MildCognitive Impairment (MCI).

Memory Assessment Clinics Questionnaire (MAC-Q).

This is a five item memory questionnaire on which subjects are asked torate on a five point scale the extent to which they have experiencedmemory loss since early adulthood when performing important tasks ofdaily life.

Geriatric Depression Scale (GDS).

This scale consists of 30 questions (e.g. Are you basically satisfiedwith your life?), each of which is checked yes or no by the subject. Ascore of 11 or higher has been shown indicative of depression.

Mini-Mental State Examination (MMSE).

This is probably the most widely used brief instrument for identifyingsubjects with dementia. The subject is asked to answer questions relatedto orientation (e.g. Where are you now?) and perform a series of simplecognitive tasks.

Wechsler Memory Scale-Revised (WMS-R)—Logical Memory Subtest I.

This is a widely used screening measure in which the subject is asked torecall verbatim a brief story just after hearing it. A score between 19and 11 (inclusive) qualifies the individual for admission to the study.In that case, or if the individual scores 10 or lower, the two followingtests are not administered.

Wechsler Memory Scale-Revised (WMS-R)—Verbal Paired Associates I.

In this test, a list of eight words is read to the subject. Some ofthese words are “easy” to associate with one another (e.g. baby-cries)and others are more abstract (e.g. cabbage-pen) and thus “hard” toassociate. After the eight pairs are read, the first word in each pairis read in a different order, and the subject is asked to provide theassociated word. This procedure is continued for three trials and the“easy” and “hard” associates are scored separately. A score of 6 or lesson the “hard” associates qualifies a potential subject for admission. Inthat case, the following test is not administered.

Wechsler Memory Scale-Revised (WMS-R)—Visual Paired Associates I.

This is the visual analog of the test described above. In this case,subjects are shown six abstract line drawings, each paired with adifferent color and then asked to indicate the appropriate colorassociated with each figure. As in the verbal paired associates test,the procedure continues for three trials. A score of 12 or lessqualifies the subject for admission in the study.

The study entailed a screening visit to determine if the subject waseligible for the study based on the inclusion/exclusion criteria. If thesubject met inclusion criteria and was not excluded based on exclusioncriteria, they were seen in the clinic within 21 days of the screeningvisit for baseline evaluation on all tests that served as outcomemeasures (Visit 2). Following baseline evaluation, subjects wereprovided with a 35 day supply of either Ketasyn™ 20 gm daily, ormatching placebo and were scheduled for a follow-up visit 30 days (±3)later (Visit 3). On Visit 3, all outcome measures were againadministered and any adverse events recorded. Ketasyn™ dosage wasincreased to 40 gm daily for the remainder of the study. Visits 4 and 5followed at 30 day (±3) intervals and on each occasion all outcomemeasures were administered and adverse events recorded. Treatment wasterminated at Visit 5. Visit 6 occurred 14 days (±3) days followingVisit 5 and all outcome measures were administered.

Evaluations at the study site were scheduled to occur 6 times: atScreen, Baseline, and post-baseline days 30, 60, 90 and 104. Clinic werescheduled in the morning, with the subject receiving their daily dose(Baseline, Days 30, 60 and 90) at the clinic following the pre-doseblood sample.

Dosing Overview.

During the double-blind period of the protocol, 79 subjects receivedKetasyn™, and 75 subjects received placebo. Ketasyn is a free flowingpowder consisting of 50% medium chain triglycerides (MCT) and 50% cornstarch. The medium chain triglycerides are composed of approximately 50%C8 and 50% C₁₀ carbon chains. Therefore, a 20 gram dose of Ketasyndelivered a 10 gram dose of MCT and a 40 gram dose delivered a 20 gramdose of MCT.

Placebo was an isocaloric mix of Long Chain Triglcyerides (LCT) andprotein. The LCT were derived from Centennial IX (Diehl Inc. OH) and iscomposed of Soybean oil emulsified with mono- and di-glycerides. Theprotein source is whey protein isolate (Davisco Inc., Eden Paire,Minn.). The nutritional profile of the Placebo is 60% protein, 31% fat,and 9% carbohydrate.

Study compound was 20 gm of Ketasyn™, or matching placebo powder mixedin one (1) glass of a liquid (i.e. preferably Ensure™; approximately 8oz) QD for the first thirty (30) days of treatment. On Day 31, eachsubject took 40 gm of Ketasyn™ or placebo QD and continue through Day90. QD doses were administered in the morning, during breakfast, excepton clinic visit days (Baseline, Days 30, 60 and 90) when the subject wasasked to undergo an overnight fast prior to the visit, and study doseswere administered in the clinic. On clinic day visits, study compoundwas mixed with low glycemic drink, (i.e. water or preferably AtkinsAdvantage™ Ready to Drink Shakes).

Genotyping.

Subjects in the study were asked to consent to genotyping for allelicvariation in the coding regions of the apolipoprotein E gene. Allelicvariants in the apolipoprotein E gene are known risk factors forAlzheimer's disease and may influence the efficacy of treatments.

Efficacy Measures.

Efficacy outcomes included:

First-Last Names Association Test (FLN(Youngjohn, J. R., et al.,First-Last Names and the Grocery List Selective Reminding Test: twocomputerized measures of everyday verbal learning, Arch ClinNeuropsychol, 1991, 6:287-300))-Immediate and Delayed Recall. In thistest from the Psychologix Battery, subjects are presented with a seriesof six pairs of first and last names that appear, one at a time on thecomputer screen. Subjects are asked to read each pair as it appears.After the last pair appears, each last name appears (in a differentorder) and the subject is asked to provide the corresponding first name.This procedure is repeated for three learning trials, which are followed30 minutes later by a delayed-recall trial. FLN is administered to thesubject at Screening, Baseline (Visit 2), and Treatment Days 30 (Visit3), 60(Visit 4), 90 (Visit 5) and 104 (Visit 6).

Serum Ketone Body Levels.

Serum Ketone body levels were elevated after treatment with medium chaintriglycerides. Ketone body levels were measured enzymatically bydetermining the level of beta-hydroxybutyrate present in the serum atboth pre-dose and 2 hours post dose. See Table 5.

TABLE 5 Placebo MCT Amount of BHB in mM BHB in mM Active* or Visit (SD)(SD) Placebo Baseline Predose 0.1120(0.0752) 0.1223(0.1064) Baseline0.1113(0.0425) 0.1885(0.1202) 20 g 2 hr Postdose Day 30 0.0868(0.0362)0.0929(0.0593) Predose Day 30 0.0994(0.0316) 0.1737(0.0815) 20 g 2 hrPostdose Day 60 0.0859(0.0447) 0.0919(0.0526) Predose Day 600.1037(0.0363) 0.2465(0.1356) 40 g 2 hr Postdose Day 90 0.0846(0.0556)0.0865(0.0593) Predose Day 90 0.0968(0.033)  0.2189(0.1605) 40 g 2 hrPostdose Day 104 0.0758(0.0325) 0.0861(0.0609) Predose *Active 50% MCTpowder.

Outcomes

FLN TC1

On Day 90, ApoE4+ subjects taking medium chain triglycerides (n=17)improved from Baseline in the FLN immediate recall task trial 1 0.89525points, while those taking Placebo (n=18) had a mean decline of −0.318(2 way ANOVA using treatment and ApoE4+ status, p-value=0.0012).

On Day 104, ApoE4+ subjects taking medium chain triglycerides (n=17)improved from Baseline in the FLN immediate recall task trial 1 0.9412points, while those taking Placebo (n=18) had a mean decline of 0.0556,(2 way ANOVA using treatment and ApoE4 status, p-value=0.0096).

Across all study visits, there was a significant correlation in ApoE4(−)subjects taking medium chain triglycerides (n=47) between Age and changefrom Baseline in the FLN immediate recall task trial 1 (r2 0.03473.p-value=0.0093). On the contrary, in the Placebo group there were nosignificant correlation in ApoE4(−) subjects (n=45) between Age andchange from Baseline in the FLN immediate recall task trial 1 (r20.009808, p-value=0.1811).

Across all study visits there was a significant difference in subjectswho identified their ethnicity as “black”. Black subjects taking mediumchain triglycerides (n=2) improved an average of 0.75 points in the FLNimmediate recall task trial, while those in the Placebo group (n=4)declined an average of −0.25 points (ANOVA using treatment in blackethnicity, p-value=0.0257).

On Day 90, there was a significant difference in subjects who identifiedtheir ethnicity as “black”. Black subjects taking medium chaintriglycerides (n=2) improved an average of 1 point in the FLN immediaterecall task trial 1, while those in the Placebo group (n=4) declined anaverage of −0.5 points (ANOVA using treatment in black ethnicity,p-value=0.0257).

On Day 90, there was a significant difference in subjects who were ofthe apolipoprotein E genotype 4/3. 4/3 subjects taking medium chaintriglycerides (n=13) improved an average of 0.76923 points in the FLNimmediate recall task trial 1, while in the Placebo group subjects ofthe genotype 4/3 (n=16) declined an average of −0.1875 points (ANOVAusing treatment in 4/3 genotype, p-value=0.0158).

FLN TC2

Across all study visits, there was a significant correlation in ApoE4(−)subjects taking medium chain triglycerides (n=47) between Age and changefrom Baseline in the FLN immediate recall task trial 2 (r2 0.024089,p-value 0.0307). On the contrary, in the Placebo group there were nosignificant correlation in ApoE4(−) subjects (n=45) between Age andchange from Baseline in the FLN immediate recall task trial 2 (r20.000267, p-value=0.8258).

Across all study visits, there was a significant correlation in ApoE4(+)subjects taking medium chain triglycerides (n=17) between Age and changefrom Baseline in the FLN immediate recall task trial 2 (r2 0.080484,p-value=0.0173). On the contrary, in the Placebo group there were nosignificant correlation in ApoE4(+) subjects (n=18) between Age andchange from Baseline in the FLN immediate recall task trial 2 (r20.012599, p-value=0.3479).

On Day 30, there was a significant correlation in ApoE4(+) subjectstaking medium chain triglycerides (n=17) between Age and change fromBaseline in the FLN immediate recall task trial 2 (r2 0.336024,p-value=0.0147). On the contrary, in the Placebo group there were nosignificant correlation in ApoE4(+) subjects (n=18) between Age andchange from Baseline in the FLN immediate recall task trial 2 on Day 30(r2 0.000087, p-value=0.9707).

Across all study visits on which subjects received study medication,there was a significant correlation in ApoE4(+) subjects taking mediumchain triglycerides (n=17) between Age and change from Baseline in theFLN immediate recall task trial 2 (r2 0.082066, p-value=0.0415). On thecontrary, in the Placebo group there were no significant correlation inApoE4(+) subjects (n=18) between Age and change from Baseline in the FLNimmediate recall task trial 2 (r2 0.010056, p-value=0.4706).

Across all study visits, there was a significant difference in subjectswho were of the apolipoprotein e genotype 4/2. 4/2 subjects takingmedium chain triglycerides (n=3) improved an average of 0.5 points inthe FLN immediate recall task trial 2, while 4/2 subjects in the Placebogroup (n=2) declined an average of −2.125 points (ANOVA using treatmentin 4/2 subjects, p-value <0.001).

FLN TC3

Across all study visits, there was a significant correlation in ApoE4(+)subjects taking medium chain triglycerides (n=17) between Age and changefrom Baseline in the FLN immediate recall task trial 3 (r2 0.109441,p-value=0.0052). In the Placebo group there were no significantcorrelation in ApoE4(+) subjects (n=18) between Age and change fromBaseline in the FLN immediate recall task trial 2 (r2 0.012996,p-value=0.3403).

On Day 30, there was a significant correlation in ApoE4(+) subjectstaking medium chain triglycerides (n=17) between Age and change fromBaseline in the FLN immediate recall task trial 3 (r2 0.242898,p-value=0.0444). On the contrary, in the Placebo group there were nosignificant correlation in ApoE4(+) subjects (n=18) between Age andchange from Baseline in the FLN immediate recall task trial 2 on Day 30(r2 0.0043652, p-value=0.4054).

Across all visits, there was a significant difference in subjects whowere of the apolipoprotein e genotype 4/2. 4/2 subjects taking mediumchain triglycerides (n=3) improved an average of 1.5833 points in theFLN immediate recall task trial 3, while 4/2 in the Placebo group (n=2)declined -2.125 points (ANOVA using treatment in 4/2 subjects, p-value<0.0007).

FLN Delayed

On Day 90, subjects taking medium chain triglycerides (n=79) improved anaverage of 0.5 points in mean change from Baseline on the FLN delayedrecall task, while those taking Placebo (n=76) showed no improvementwith a mean change from Baseline of 0.0 (ANCOVA comparing means,treatment, age, site, treatment*site interaction and baseline covariatein model, p-value=0.0416).

On Day 90, ApoE4-subjects taking medium chain triglycerides (N=47)improved an average of 0.68574 points in mean change from Baseline inthe FLN delayed task, while those taking Placebo (n=45) declined anaverage of −0.08918 points (2 way ANOVA, treatment and ApoE4 statusp-value=0.0124).

On Day 90, ApoE 3/3 subjects taking medium chain triglycerides (n=37)improved an average of 0.8108 points in change from Baseline in the FLNdelayed task, while 3/3 subjects on Placebo (n=37) improved only anaverage of 0.1081 points (ANOVA using treatment in 3/3 subjects,p-value=0.0393).

On Day 90, female subjects taking medium chain triglycerides (n=46)improved an average of 0.667 points from Baseline in the FLN delayedtask, while those taking Placebo (n=51) declined an average of −0.184points from Baseline in the FLN delayed task (ANOVA using treatment infemale subjects, p-value=0.0068).

Across all visits, ApoE 4/2 subjects taking medium chain triglycerides(n=3) improved an average of 1.5833 points in change from Baseline inthe FLN delayed task, while those 4/2 subjects taking Placebo (n=2) hada mean decline of −2.125 points (ANOVA using treatment in 4/2 subjects,p-value=0.0007).

Name-Face Association Test (NFA)—Immediate and Delayed Recall

In this test, also from the Psychologix Battery, subjects are presentedwith a live video presentation of individuals introducing themselves bycommon first names. After a series of introductions, recall is assessedby showing the same individuals in a different order and asking thesubject to provide the name of each person. There are two learningtrials in which fourteen name-face pairs are presented and recall isassessed. Delayed recall is assessed thirty minutes later. NFA isadministered to subjects at Screening, Baseline (Visit 2), and TreatmentDays 30 (Visit 3), 60 (Visit 4), 90 (Visit 5) and 104 (Visit 6).

Outcomes

NFA 14A

Across all study visits, there was a significant correlation in subjectstaking medium chain triglycerides (n=79) between Age and change fromBaseline in the NFA immediate recall task trial A (r2 0.013446.p-value=0.0364). On the contrary, in the Placebo group (n=76) there wereno significant correlation in subjects between Age and change fromBaseline in the NFA immediate recall task trial A (r2 0.0.000005,p-value=0.9693).

Across all study visits, there was a significant correlation inApoE4-subjects taking medium chain triglycerides (n=47) between Age andchange from Baseline in the NFA immediate recall task trial A (r20.033094. p-value=0.0111). On the contrary, in the Placebo group (n=45)there were no significant correlation in subjects between Age and changefrom Baseline in the NFA immediate recall task trial A (r2 0.005132,p-value=0.3339).

NFA 14B

Across all study visits, ApoE4-subjects taking medium chaintriglycerides (n=47) improved an average of 0.639 points on NFAimmediate recall task trial B, while those taking Placebo (n=45)declined an average of −0.136 points (ANOVA using treatment inApoE4-subjects, p=0.0048).

On Day 30, ApoE4-subjects taking medium chain triglycerides (n=47)improved an average of 0.40426 points on NFA immediate recall task trialB, while those taking Placebo (n=45) declined an average of −0.8 points(ANOVA using treatment in ApoE4-subjects, p=0.0225).

On Day 90, there was a significant correlation in subjects taking mediumchain triglycerides (n=79) between Age and change from Baseline in theNFA immediate recall task trial B (r2 0.051901, p-value=0.0435). On thecontrary, in the Placebo group (n=75) there were no significantcorrelation in subjects between Age and change from Baseline in the NFAimmediate recall task trial B (r2 0.015814, p-value=0.2791).

Across all study visits, there was a significant correlation in subjectstaking medium chain triglycerides (n=79) between Age and change fromBaseline in the NFA immediate recall task trial B (r2 0.01722.p-value=0.0178). On the contrary, in the Placebo group (n=76) there wereno significant correlation in subjects between Age and change fromBaseline in the NFA immediate recall task trial B (r2 0.000005,p-value=0.9678).

Across all study visits, there was a significant correlation inApoE4-subjects taking medium chain triglycerides (n=47) between Age andchange from Baseline in the NFA immediate recall task trial B (r20.0261. p-value=0.0244). On the contrary, in the ApoE4-Placebo group(n=45) there were no significant correlation in subjects between Age andchange from Baseline in the NFA immediate recall task trial B (r20.005845, p-value=0.3023).

NFA 14D

Across all study visits, there was a significant correlation in subjectstaking medium chain triglycerides (n=79) between Age and change fromBaseline in the NFA delayed recall task (r2 0.017714, p-value=0.0162).On the contrary, in the Placebo group (n=76) there were no significantcorrelation in subjects between Age and change from Baseline in the NFAdelayed recall task (r2 0.005497, p-value=0.1922).

Telephone Dialing Test (TDT)

This is a test of “working memory” from the Psychologix Battery, inwhich the individual must hold information in mind only long enough toperform a task. In this case the task is to dial a seven or ten digitnumber on a touch screen representation of a telephone after it hasappeared on the testing screen. On some trials the individual encountersinterference in the form of a “busy signal” and must redial the numberfrom memory. TDT is administered to subjects at Screening, Baseline(Visit 2), and Treatment Days 30 (Visit 3), 60 (Visit 4), 90 (Visit 5)and 104 (Visit 6).

TDT without Interference

Across all visits, there was a significant difference in subjects whowere taking medium chain triglycerides and had six years of education.Subjects with 6 years of education taking medium chain triglycerides(n=8) improved an average of 0.37966 points in the TDT withoutinterference trial, while subjects with six years of education takingthe Placebo (n=4) declined −0.04197 points (ANOVA using treatment in 4/2subjects, p-value <0.0314).

TDT Before Interference

Across all visits, there was a significant correlation between age andchange from Baseline in the TDT before interference trial in ApoE4+subjects who were taking medium chain triglycerides. There was asignificant correlation in ApoE4+ subjects taking medium chaintriglycerides (n=17) between Age and change from Baseline in the TDTbefore interference trial (r2 0.068747, p-value=0.0283). On thecontrary, in the Placebo group (n=18) there were no significantcorrelation in ApoE4+ subjects between Age and change from Baseline (r20.006418, p-value=0.5035).

Across all visits, there was a significant correlation between age andchange from Baseline in the TDT before interference trial in subjectswho identified themselves as “white” and were taking medium chaintriglycerides. There was a significant correlation in white subjectstaking medium chain triglycerides (n=72) between Age and change fromBaseline in the TDT before interference trial (r2 0.015959,p-value=0.0303). On the contrary, in the Placebo group (n=69) there wereno significant correlation in white subjects between Age and change fromBaseline (r2 0.000374, p-value=0.7496).

Across all visits, there was a significant correlation between age andchange from Baseline in the TDT before interference trial in subjectswho were male and identified themselves as “white” and were takingmedium chain triglycerides. There was a significant correlation in whitemale subjects taking medium chain triglycerides (n=35) between Age andchange from Baseline in the TDT before interference trial (r2 0.03163,p-value=0.0406). On the contrary, in the Placebo group (n=27) there wereno significant correlation in white male subjects between Age and changefrom Baseline (r2 0.007459, p-value=0.3978).

Across all visits, there was a significant correlation between age andchange from Baseline in the TDT before interference trial in subjectswho were male, of the apolipoprotein e genotype 3/3, and were takingmedium chain triglycerides. There was a significant correlation in 3/3male subjects taking medium chain triglycerides (n=15) between Age andchange from Baseline in the TDT before interference trial (r2 0.03163,p-value=0.0406). On the contrary, in the Placebo group (n=11) there wereno significant correlation in white male subjects between Age and changefrom Baseline (r2 0.007459, p-value=0.3978).

TDT after Interference

Across all visits, there was a significant correlation between age andchange from Baseline in the TDT after interference trial in subjects whowere male, ApoE4-, and were taking medium chain triglycerides. There wasa significant correlation in ApoE4-male subjects taking medium chaintriglycerides (n=23) between Age and change from Baseline in the TDTbefore interference trial (r2 0.076249, p-value=0.0077). On thecontrary, in the Placebo group (n=14) there were no significantcorrelation in male, ApoE4-subjects between Age and change from Baseline(r2 0.000003, p-value=0.9892).

Across all visits, there was a significant correlation between age andchange from Baseline in the TDT after interference trial in subjects whowere male, ApoE 3/3, and were taking medium chain triglycerides. Therewas a significant correlation in ApoE 3/3 male subjects taking mediumchain triglycerides (n=23) between Age and change from Baseline in theTDT before interference trial (r2 0.13174, p-value=0.0051). On thecontrary, in the Placebo group (n=15) there were no significantcorrelation in male ApoE 3/3 subjects between Age and change fromBaseline (r2 0.008633, p-value=0.5486).

Visual Sequence Comparison (VSC; (Kay, G., Cogscreen: ProfessionalManual, 1995))

VSC simultaneously presents the respondent with two alphanumericstrings, one on the right and the other on the left half of the screen.The respondent selects [SAME] or [DIFFERENT] for each pair, indicatingwhether the same characters are presented in the same order for bothsequences. The strings vary in length from four to eight items. For eachpair, the strings may differ by one or two items. Half of the 20sequence pairs present the same sequence, and half present a differentsequence. Performance measures include the speed (VSC Speed; VSCRTC) andaccuracy (VSC Accuracy; VSCACC) of responses, and the number of problemscorrectly completed per minute (VSC Thruput; VSCPUT). Most subjectscomplete almost all problems, therefore Thruput is considered the bestmeasure of efficacy. Mental functions addressed by this test includevisual attention, working memory, verbal-sequential processing, andvisual-perceptual speed.

The VSC is administered to subjects at Screening, Baseline (Visit 2),and Treatment Days 30 (Visit 3), 60 (Visit 4), 90 (Visit 5) and 104(Visit 6).

VSC Thruput

Across all study visits, there was a significant difference in subjectswith 2 years of education on VSC thruput task. Subjects with three yearsof education taking medium chain triglycerides (n=1) improved an averageof 3.427 points in the VCS thruput task, while subjects with three yearsof education in the Placebo group (n=2) declined an average of −0.346points (ANOVA using treatment in subjects with 3 years of education,p-value=0.0234).

DAT Dual Task (DAT Dual)

The second DAT task is the Visual Sequence Comparison task, which isperformed simultaneously with the visual monitoring task. Response speedis measured for both the monitoring task (DAT Indicator Dual Speed;DATDRTC) and the visual sequence comparison task (DAT SequenceComparison Speed; DATSCRTC). Accuracy (DAT Sequence ComparisionAccuracy; DATSCACC) and number of items correctly completed per minute(DAT Sequence Comparison Thruput; DATSCPUT) are measured for thesequence comparison task in the dual condition. DAT Indicator DualPremature Responses (DATDPRE) represents the number of prematurecentering responses in the simultaneous condition. When the two tasksare presented simultaneously, the test assesses divided attention,working memory, and visual-motor and visual-perceptual speed. Thruput isconsidered the most accurate measure. The DAT-dual is administered tosubjects at Screening, Baseline (Visit 2), and Treatment Days 30 (Visit3), 60 (Visit 4), 90 (Visit 5) and 104 (Visit 6).

DAT Thruput

Across all visits, there was a significant correlation between age andchange from Baseline in the DAT Thruput score in subjects who weretaking medium chain triglycerides. There was a significant correlationin subjects taking medium chain triglycerides (n=79) between Age andchange from Baseline in the DAT Thruput score (r2 0.025075,p-value=0.0042). On the contrary, in the Placebo group (n=76) there wereno significant correlation in subjects between Age and change fromBaseline (r2 0.003796, p-value=0.2787).

Across all visits, there was a significant correlation between age andchange from Baseline in the DAT Thruput score in male subjects who weretaking medium chain triglycerides. There was a significant correlationin male subjects taking medium chain triglycerides (n=35) between Ageand change from Baseline in the DAT Thruput score (r2 0.042436,p-value=0.0042). On the contrary, in the Placebo group (n=27) there wereno significant correlation in subjects between Age and change fromBaseline (r2 0.005274, p-value=0.4509).

Across all visits, there was a significant correlation between age andchange from Baseline in the DAT Thruput score in ApoE4-subjects who weretaking medium chain triglycerides. There was a significant correlationin ApoE4-subjects taking medium chain triglycerides (n=47) between Ageand change from Baseline in the DAT Thruput score (r2 0.049976,p-value=0.0017). On the contrary, in the Placebo group (n=45) there wereno significant correlation in subjects between Age and change fromBaseline (r2 0.01203, p-value=0.1383).

MTS

Subjects are presented with a checkerboard (4×4) made up of purple andyellow squares. The checkerboard disappears and is replaced by oneidentical and one similar board. Subjects are asked to identify theidentical board. Response speed, accuracy and efficiency are measured.Performance measures include the speed (MTS Speed) and accuracy (MTSAccuracy; MTSACC) of responses, and the number of problems correctlycompleted per minute (MTS Thruput; MTSPUT). Most subjects completealmost all problems, therefore Thruput is considered the best measure ofefficacy. Mental functions addressed by this test include visualattention, working memory, verbal-sequential processing, andvisual-perceptual speed. The MTS is administered to subjects atScreening, Baseline (Visit 2), and Treatment Days 30 (Visit 3), 60(Visit 4), 90 (Visit 5) and 104 (Visit 6).

On Day 90, there was a significant difference in subjects who identifiedthemselves as “black” on MTS thruput task. Black subjects taking mediumchain triglycerides (n=2) improved an average of 15.47 points in the MTSthruput task, while black subjects in the Placebo group (n=4) improvedonly an average of 3.28 points (ANOVA using treatment in black subjects,p-value=0.0125).

Across all study visits, there was a significant difference in subjectswith 3 years of education on MTS Thruput task. Subjects with three yearsof education taking medium chain triglycerides (n=2) improved an averageof 12.46 points in the MTS thruput task, while subjects with three yearsof education in the Placebo group (n=1) improved only an average of 3.9points (ANOVA using treatment in subjects with 3 years of education,p-value=0.0216).

Across all study visits, there was a significant difference in subjectswith 6 years of education on MTS Thruput task. Subjects with six yearsof education taking medium chain triglycerides (n=22) improved anaverage of 2.99 points in the MTS thruput task, while subjects with sixyears of education in the Placebo group (n=16) improved only an averageof 0.602 points (ANOVA using treatment in subjects with 6 years ofeducation, p-value=0.0313).

Across all study visits, there was a significant difference inApoE4-subjects with 7 years of education on MTS Thruput task.ApoE4-subjects with 7 years of education taking medium chaintriglycerides (n=5) improved an average of 4.879 points in the MTSThruput task, while subjects with six years of education in the Placebogroup (n=2) declined an average of −6.713 points (ANOVA using treatmentin subjects with 6 years of education, p-value <0.001).

Conclusions.

The present examples 3, 4 and 5 disclose the novel finding that mediumchain triglycerides improved measures of memory, attention and reactiontime in an elderly population. This population was free of any dementingillnesses and was categorized as having age associated memory impairment(AAMI). AAMI is considered to occur during the natural course of aging.Mean age for the population in this study was 65.0 years of age. Minimumage was 50, maximum age was 83. The present invention discloses thesurprising finding that treatment with 10-20 grams of medium chaintriglycerides given once a day is sufficient to improve several measuresof brain function. Improvement was found in memory tasks, such as theFirst Last Name (FLN) task and the Name Face Association (NFA) task.Improvement was also found in attention tasks such as the Dual AttentionTask (DAT) and measures of visual processing such as the Matching toSample (MTS) task. Together these results teach that providingadditional energy reserves to the elderly brain improves a variety ofcognitive activities.

Example 6 Formulations

Boost™ with fiber nutritional beverage (Mead Johnson Nutritionals) andsimilar products such as Ensure™ have the following general aspects andingredients. Amounts are per 8 fl. oz. container, which is planned toprovide 20-25% of the daily requirements. Tailoring the followingformulation for use in subjects with age associated memory impairmentwould be very beneficial.

Calories, kcal 250

Calories from fat 70

Protein, g 11

Fat, g 8

Saturated fat, g 1.5

Carbohydrate, g 33

Dietary Fiber, g 3

Sugars, g 16

Water, g 200

Vitamin A, IU 830

Vitamin D, IU 100

Vitamin E, IU 5

Vitamin K, .mcg 23

Vitamin C, mg 30

Folic Acid, .mcg 100

Thiamin, mg 0.37

Riboflavin, mg 0.43

Niacin, mg 5

Vitamin B6, mg 0.5

Vitamin B12, .mcg 1.5

Biotin, .mcg 75

Pantothenic Acid, mg 2.5

Calcium, mg 200

Phosphorus, mg 167

Iodine, .mu.g 25

Iron, mg 3

Magnesium, mg 67

Copper, mg 0.33

Zinc, mg 3.3

Manganese, mg 0.42

Chloride, mg 330

Potassium, mg 330

Sodium, mg 170

The present invention describes a novel formulation wherein the aboveformula is supplemented with about 1 to 80 grams for medium chaintriglycerides and about 10 to 2000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 5 to 50 grams of medium chaintriglycerides and about 50 to 1000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 10 to 30 grams of medium chaintriglycerides and about 100 to 500 mg of L-carnitine oracetyl-L-carnitine.

Example 7 Formulations

Boost™. High Protein Powder (Mead Johnson Nutritionals) or similarproducts are high-protein, low-fat nutritional powders that can be mixedwith skim milk or water. About 54 g of the powder is to be mixed with 8fluid ounces (fl. oz) of water, and is said to provide at least 25% ofthe US RDA of most essential vitamins and minerals in 200 calories. Ithas virtually no fat. When mixed with skim milk, the mixture providesabout 290 calories and about 33% of the US RDA of most essentialvitamins and minerals. Tailoring the following formulation for use insubjects with age associated memory impairment would be very beneficial.

The water mixture provides the following:

Protein, g 13

Carbohydrate, g 36

Sugars, g 35

Water, g 240

Vitamin A, IU 1290

Vitamin D, IU 33

Vitamin E, IU 10

Vitamin C, mg 20

Folic Acid, .mcg 133

Thiamin, mg 0.4

Riboflavin, mg 0.2

Niacin, mg 6.8

Vitamin B6, mg 0.55

Vitamin B12, .mcg 1

Biotin, .mcg 93

Pantothenic Acid, mg 2.7

Calcium, mg 290

Phosphorus, mg 250

Iodine, .mcg 40

Iron, mg 6

Magnesium, mg 105

Copper, mg 0.7

Zinc, mg 4

Manganese, mg 1

Chloride, mg 220

Potassium, mg 560

Sodium, mg 189

The present invention describes a novel formulation wherein the aboveformula is supplemented with about 1 to 80 grams for medium chaintriglycerides and about 10 to 2000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 5 to 50 grams of medium chaintriglycerides and about 50 to 1000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 10 to 30 grams of medium chaintriglycerides and about 100 to 500 mg of L-carnitine oracetyl-L-carnitine.

Example 8 Formulations

Boost™ Pudding (Mead Johnson) or similar products are labeled forintended use in geriatric patients, malnourished cancer patients andpersons desiring weight control. The current formulation provides 240calories in 5 ounces, low sodium and cholesterol, and 15-20% of the USRDA requirements for most vitamins and minerals. Tailoring the followingformulation for use in subjects with age associated memory impairmentwould be very beneficial.

Protein, g 7

Fat, g 9

Saturated Fat, g 1.5

Sugars, g 27

Water, g 92

Vitamin A, IU 750

Vitamin D, IU 60

Vitamin E, IU 4.5

Vitamin C, mg 9

Folic Acid, .mcg 60

Thiamin, mg 0.23

Riboflavin, mg 0.26

Niacin, mg 3

Vitamin B6, .mcg 300

Vitamin B12, .mcg 0.9

Biotin, .mcg 45

Pantothenic Acid, mg 1.5

Calcium, mg 220

Phosphorus, mg 220

Iodine, .mcg 23

Iron, mg 2.7

Magnesium, mg 60

Copper, mg 0.3

Zinc, mg 2.3

Chloride, mg 200

Potassium, mg 320

Sodium, mg 120

The present invention describes a novel formulation wherein the aboveformula is supplemented with about 1 to 80 grams for medium chaintriglycerides and about 10 to 2000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 5 to 50 grams of medium chaintriglycerides and about 50 to 1000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 10 to 30 grams of medium chaintriglycerides and about 100 to 500 mg of L-carnitine oracetyl-L-carnitine.

Example 9 Formulations

Nutritional bars have been developed for a variety of diets and activitylevels (e.g., Luna™, from Clif Bar, Inc., Berkeley, Calif.) but have noeffect on cognitive performance. An example of such a nutritional bar isshown below. Percents are the portion of minimum daily requirements.Tailoring the following formulation for use in subjects with ageassociated memory impairment would be very beneficial.

Total Fat, g 4

Saturated Fat, g 3

Sodium, mg 50

Potassium, mg 90

Total Carbohydrate, g 26

Dietary Fiber, g 1

Sugars, g 15

Other Carbs, g 10

Protein, g 10

Vitamin A, % 25

Vitamin C, % 100

Calcium, % 35

Iron, % 35

Vitamin K, % 100

Thiamin, % 100

Riboflavin, % 100

Niacin, % 100

Vitamin B6, % 100

Folic Acid, % 100

Vitamin B12, % 100

Biotin, % 100

Pantothenic Acid, % 100

Phosphorus, % 35

Iodine, % 35

Zinc, % 35

Selenium, % 35

Copper, % 35

Manganese, % 35

Chromium, % 35

Molybdenum, % 35

The present invention describes a novel formulation wherein the aboveformula is supplemented with about 1 to 80 grams for medium chaintriglycerides and about 10 to 2000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 5 to 50 grams of medium chaintriglycerides and about 50 to 1000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 10 to 30 grams of medium chaintriglycerides and about 100 to 500 mg of L-carnitine oracetyl-L-carnitine.

Example 10 Formulations

A formulation of flavored gelatin (e.g., JELL-O™) provides 130 caloriesin 227 g. Tailoring the following formulation for use in active elderswould be highly beneficial. Percents are the portion of minimum dailyrequirements.

Protein, g 2

Fat, g 0

Saturated Fat, g 0

Sugars, g 31

Vitamin A, % 6

Vitamin C, % 4

Calcium, % 0

Iron, % 2

Sodium, mg 75

Gelatin flavors can include: apricot, berry blue, black cherry, cherry,cranberry, cranberry raspberry, cranberry strawberry, grape, lemon,lime, mandarin orange, mango, mixed fruit, orange, peach, peach passionfruit, island pineapple, raspberry, strawberry, strawberry banana,strawberry kiwi, watermelon, wild berry, and wild strawberry, amongothers.

The present invention describes a novel formulation wherein the aboveformula is supplemented with about 1 to 80 grams for medium chaintriglycerides and about 10 to 2000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 5 to 50 grams of medium chaintriglycerides and about 50 to 1000 mg of L-carnitine oracetyl-L-carnitine. Or more preferably, 10 to 30 grams of medium chaintriglycerides and about 100 to 500 mg of L-carnitine oracetyl-L-carnitine.

All publications and patent applications cited in this specification areherein incorporated by reference as if each individual publication orpatent application were specifically, and individually, indicated to beincorporated by reference.

While the invention has been described with reference to exemplaryembodiments, it will be understood by those skilled in the art thatvarious changes may be made and equivalents may be substituted forelements thereof without departing from the scope of the invention. Inaddition, many modifications may be made to adapt a particular situationor material to the teachings without departing from the essential scopethereof. Therefore, it is intended that the invention not be limited tothe particular embodiment disclosed as the best mode contemplated forcarrying out this invention, but that the invention will include allembodiments falling within the scope of the appended claims.

What is claimed is:
 1. A method of treatment for Age-Associated MemoryImpairment (AAMI), comprising administration comprising the steps of:identifying a mammal having AAMI; and administering to the mammal acomposition comprising a compound selected from the group consisting ofacetoacetate, D-β-hydroxybutyrate, an ester of acetoacetate, and anester of D-β-hydroxybutyrate, wherein the compound is effective toinduce hyperketonemia, in an amount effective for the treatment of AAMI.2. The method of claim 1, wherein the compound is an ester of a compoundselected from the group consisting of D-β-hydroxybutyrate andacetoacetate and a compound selected from the group consisting of amonohydric, dihydric, or trihydric alcohol.
 3. The method of claim 2,wherein the compound is a trihydric alcohol ester of D-β-hydroxybutyrateor a trihydric alcohol ester of acetoacetate.
 4. The method of claim 3,wherein the compound comprises a glycerol ester of acetoacetate or aglycerol ester of D-β-hydroxybutyrate.
 5. The method of claim 4, whereinthe compound is acetoacetylglycerol.
 6. The method of claim 2, whereinthe compound is a dihydric alcohol ester of D-β-hydroxybutyrate or adihydric alcohol ester of acetoacetate.
 7. The method of claim 6,wherein the compound comprises R-1-3-butanediol ester of acetoacetate orR-1,3-butanediol ester of D-β-hydroxybutyrate.
 8. The method of claim 1,wherein the composition further comprises glucose.
 9. The method ofclaim 1 wherein the composition increases the circulating concentrationof at least one type of ketone body in the mammal.
 10. The method ofclaim 9, wherein the amount of D-β-hydroxybutyrate is raised in theblood of the mammal.
 11. The method of claim 10, wherein the amount ofD-β-hydroxybutyrate is raised to between about 0.1 millimolar to about10 millimolar at about two hours post administration.
 12. The method ofclaim 10, wherein the amount of D-β-hydroxybutyrate is raised to betweenabout 0.15 millimolar to 0.3 millimolar at about two hours postadministration.
 13. The method of claim 10 wherein urinary excretionlevel of D-β-hydroxybutyrate is from about 5 to about 160 mg/dL.
 14. Themethod of claim 1 wherein the composition is administered at a dose ofabout 0.05 g/kg/day to about 10 g/kg/day.
 15. The method of claim 1wherein the composition is administered at a dose of about 0.1 g/kg/dayto about 2 g/kg/day.
 16. The method of claim 1, wherein the compositionis a ready-to-drink beverage, powdered beverage formulation, nutritionalor dietary supplement selected from the group consisting of gelatincapsule or tablet, suspension, parenteral solution, or a food productformulated for human consumption.
 17. The method of claim 1, wherein themammal is a human.
 18. The method of claim 1, wherein the administeringstep is on a regular basis comprising at least once daily.
 19. Themethod of claim 1, comprising the further step of determining the ApoEstatus of the mammal and selecting the mammal for treatment if themammal is ApoE4(−).
 20. The method of claim 7, wherein efficacy fortreatment of AAMI is determined by results from at least oneneuropsychological test.
 21. The method of claim 20, wherein theneuropsychological test is selected from the group consisting ofClinical Global Impression of Change (CGIC), Rey Auditory VerbalLearning Test (RAVLT), First-Last Names Association Test (FLN),Telephone Dialing Test (TDT), Memory Assessment Clinics Self-RatingScale (MAC-S), Symbol Digit Coding (SDC), SDC Delayed Recall Task (DRT),Divided Attention Test (DAT), Visual Sequence Comparison (VSC), DAT DualTask (DAT Dual), and Geriatric Depression Scale (GDS).